Final Report Summary - INNOVABALT (Strengthening the research and innovation capacities of the Latvian Institute of Organic Synthesis, the leading Baltic regional centre for drug discovery)
Executive Summary:
Latvian Institute of Organic Synthesis (LIOS) has finished the implementation of the FP7 project InnovaBalt: Strengthening the research and innovative capacities of the Latvian Institute of Organic Synthesis, the leading Baltic regional centre for drug discovery.
The general goal of this project was to unlock and to develop the existing excellence in the LIOS and to become active player in the ERA (European Research Area). The objectives of the InnovaBalt were achieved through a set of measures:
• exchange of know-how and experience with EU partnering organizations;
• recruitment of experienced researchers and technical staff;
• upgrading of research infrastructure;
• elaboration of a strategic IP development plan for IP management
and innovation capability building;
• dissemination and communication activities, the increasing of visibility of the
InnovaBalt activities at regional, national and EU levels.
The fulfilment of the InnovaBalt objectives were evaluated by external experts to define specific actions for the future sustainability of LIOS.
The main results of InnovaBalt project:
1. During the InnovaBalt collaboration with 50 research institutions was implemented. In total 62 incoming visits of recognized researchers and 76 outgoing visits to partnering organizations were carried out.
2. InnovaBalt project supported recruitment of 12 experienced and 7 post-doctoral researchers. It should be emphasized that 6 of them were Latvian researchers previously working at the leading European research institutions. Recruitment of these researchers decreased brain-drain which was indicated as a threat in the SWOT analysis of LIOS.
3.Researchers involved in the InnovaBalt project activities have published 34 scientific articles in SCI journals.
4. The equipment acquired in the InnovaBalt has been intensively used and upgraded. Equipment includes 7 devices and systems, which will strengthen LIOS infrastructure in nanotechnology, protein crystallography, imaging in living animals in real time, fluorescent spectroscopy and computing.
5. During the InnovaBalt project implementation 12 international events have been organised.
6. LIOS patent portfolio has been updated and strengthened, future strategy developed. IP manager, recruited during the InnovaBalt, continues to be employed by LIOS.
7. Visibility of LIOS has been reached through the regular participation and exploitation of research results in the international conferences and by the organization of international events in Latvia. Manager of the InnovaBalt, Professor Maija Dambrova, presented experience and results of the InnovaBalt project in 3 European-level events:
- the Workshop during WIRE 2015 „Week of Innovations regions in Europe”, Riga, 3.06. 2015 (Latvia’s Presidency event),
- the Workshop „Contribution of "Research Potential" (REGPOT) and "Regions of Knowledge" (ROK), the way forward thanks to synergies between EU policies/funds”, Brussels , 07.12.2015.
- Conference “Bridging the Divide in European Health Research and Innovation”, Brussels, 20.10.2016.
The synergy of the InnovaBalt project with different EU Structural Fund activities has been achieved.
The InnovaBalt project contributed to the regional economical development through strengthening tight collaboration with industry and innovative drug discovery projects in LIOS. The InnovaBalt project activities are expected to have long-term social and economic impacts in relation to transformation of the national economy and growth priorities defined in the Latvian Smart Specialization Strategy, especially in RIS3 area of specialization: 2. biomedicine, medical technologies, biopharmacy and biotechnologies.
Website: www.innovabalt.eu
Virtual tour about OSI: www.osi.lv/en
Video: https://www.youtube.com/watch?v=FQEzm4XtE8I&feature=youtu.be
Project Context and Objectives:
The InnovaBalt was a 4.7 million project supported by the FP7. The FP7 “Research Potential” (REGPOT) Programme was created to unlock and develop existing excellence in the EU’s Convergence regions and Outermost regions, and to help research actors in these regions to become active players in the ERA (European Research Area). The priority was to increase the research potential in these regions and improve their knowledge and technological processes – contributing to the growth, productivity and employment of these regions.
Duration of the InnovaBalt was from 01.09.2013 till 28.02.2017. During the InnovaBalt project period the Action plan based on SWOT analysis of LIOS was implemented. The strategic objective of the InnovaBalt was to strengthen the multidisciplinary research capacities, management of intellectual property as well as human resources in the innovative drug discovery at LIOS.
The short term objectives of the InnovaBalt project were following:
1. To establish and to strengthen the long-lasting scientific collaboration and strategic partnership between LIOS and outstanding research institutions in ERA;
2. To increase the innovation and improving of management of intellectual property through collaboration and attraction of external professionals;
3. To upgrade the research infrastructure at LIOS to promote the capacity for the high level research on innovative drug development;
4. To increase the visibility of LIOS in ERA;
5. To ensure the synergy between research on innovative drug development and end-users (SMEs, industry, clinics, patients’ organizations);
6. To reinforce the strategic development of LIOS to improve the response to socio-economic needs of Baltic region in health area.
The implementation of Action Plan was carried out by the coherent set of measures structured into 8 work packages (WP).
WP1. Exchange of experience and know-how (via international two-way secondments of experienced and young researchers of LIOS with researchers from excellent and complementary European research centres).
Objectives of WP1:
-) to promote the exchange of experience and to know-how,
-) to build the capacity of LIOS researchers by obtaining the necessary knowledge and skills,
-) to strengthen the networking with partner organizations to ensure the long lasting further cooperation.
WP2. Strengthening of the research potential of human resources
Objectives of WP2:
-) to increase the LIOS research capacity and experience in new directions of drug discovery by recruitment of experienced researchers,
-) to increase the international-level transfer process of accumulated knowledge and technologies through the reintegration of experienced researchers from abroad,
-) to increase the research potential of existing laboratories by recruitment of post-doctoral researchers.
WP3. Renewal of research equipment
Objectives of WP3:
-) to acquire a modern equipment and tools necessary for innovative drug development;
-) to upgrade the research equipment of LIOS.
Description of work and role of partners
WP4. Organization of seminars and conferences
Objectives of WP4:
-) to facilitate the knowledge transfer at the national, regional and international levels, to ensure the synergy between research on innovative drug development and end users,
-) to increase the visibility of LIOS by dissemination of the results of LIOS researchers in organic chemistry, medicinal chemistry of heterocycles, structure-activity relationships, experimental chemotherapy and pharmacology to the international scientific community. -) to strengthen the long-lasting scientific collaboration between LIOS and partnering organisations in ERA.
WP5. Improving the management of Intellectual Property and enhancement of innovation potential
Objectives of WP5:
-) to increase the innovation potential at the national, regional and trans/international levels to give contribution to the economic growth in the area of innovative medicine,
-) to improve knowledge of researchers (both early stage and experienced) and stakeholders from the pharmaceutical industry on Intellectual property rights (IPR), their management and technology transfer issues,
-) to strengthen the long-lasting collaboration between LIOS and end-users (industry) to ensure the technology transfer for the innovative drug development targeted to the challenges in health area.
WP6. Dissemination and promotional activities
Objectives of WP6:
-) to promote the InnovaBalt project within the scientific community of Europe to ensure the long lasting integration of LIOS in ERA,
-) to disseminate the information on advanced innovative medicine development to the industry sector and other stakeholders,
-) to prove the information for society on topicalities in innovative drug development and results of the InnovaBalt,
WP7. External Assessment of LIOS
Objectives of WP7:
-) to evaluate the implementation of the project, including a new SWOT analysis and updated Strategy relevant to the current situation,
-) to get an independent opinion about LIOS capacity (including management and IPR management) for its further development,
-) to optimize LIOS integration in ERA by increased contribution to regional economic and social development and for better participation in FP projects
WP8. Management
Objectives of WP8:
-) to set up the appropriate monitoring, coordination and communication procedures in order to ensure that project is implemented in a timely and cost effective manner in accordance with applicable EC guidelines and national legislation rules,
-) to ensure that EC financial and administrative procedures are respected and reports and cost statements are provided in time.
The InnovaBalt project implementation was well aligned to all major activities of the LIOS strategic research program:
-) new drug targets, medicinal chemistry,
-) development of synthesis methodology, scale-up and optimisation,
-) in silico modelling, structure biology,
-) biophysical and biochemical screening, bioanalytical assays,
-) in vitro, in vivo activity testing systems, toxicity, pharmacokinetis, ADME.
External experts nominated by the EC evaluated the InnovaBalt project as excellent in terms of results and increase in research quality performed at the LIOS. The new equipment and the secondments supported by the InnovaBalt, where the driving forces for the LIOS researchers to establish and/or reinforce international collaborations with the pharmaceutical industry and top research groups from academia, leading to an increase of the number of publications in high impact factors journals in the areas of chemistry/structural biology/pharmacology. The InnovaBalt also allowed the LIOS to attract young Latvian researchers that were abroad, which brought their acquired know-how to the institute.
Project Results:
Please provide a description of the main S & T results/foregrounds. The length of this part cannot exceed 25 pages.
Implementation of the InnovaBalt (recruited researchers, upgraded scientific equipment, exchange of experience, trainnings of staff) has essentially increased the research capacities and capabilities of LIOS. New collaborative research projects started since 2015 reflect the main S&T results of the InnovaBalt.
Horizon 2020 projects
1. Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets, www.integrate-etn.eu
Acronym: INTEGRATE, Contract number: 642620
Funding scheme: MSCA-ITN-ETN – Training Networks
Implementation period: 01.01.2015. – 31.12.2018
Costs for Latvian partner: 223 577,64 EUR
Project coordinator: University of Parma, Italy
Project partners: University of Helsinki (Finland), University of Eastern Finland (Finland), Latvian Institute of Organic Synthesis (Latvia), The Chancellor, Masters and Scholars of the University of Cambridge (UK), University of Ljubljana (Slovenia), Taros Chemicals GMBH & CO KG (Germany), University of Antwerp (Belgium), Aptuit, Verona SRL (Italy), Fraunhofer Gesellschaft zur Forderung der Angewandten Forshung EV (Germany).
Summary
Antimicrobial resistance is posing a continuously-rising threat to global health. The INTEGRATE project has assembled a team of 10 beneficiaries from eight EU member states, encompassing both academic and non-academic sectors and different disciplines, to form a consortium committed to training Early Stage Researchers (ESRs) in the discovery and preclinical validation of novel Gram-negative antibacterial agents and antibacterial targets. The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure is accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. The intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.
2. Peptidomimetics with photocontrolled biological activity www.pelico.org
Acronym: PELICO, Contract number 690973
Funding scheme: MSCA-RISE – Research and Innovation Staff exchange
Implementation period: 01.01.2016. – 31.12.2019.
Costs for Latvian partner: 103 500 EUR
Project coordinator: Enamine, Limited Liability Company (Ukraine)
Project partners: Karlsruhe Institute of Technology (Germany),
Latvian Institute of Organic Synthesis (Latvia),
The Chancellor, Masters and Scholars of the University of Cambridge (UK).
Summary
The expertise, resources and specific knowledge of all participating parties will be combined to achieve a breakthrough in design, synthesis and application of peptide analogues (peptidomimetics) possessing photo-controlled biological activities, with special emphasis on anti-microbial and anti-cancer activities. The main idea behind the Project consists in chemical incorporation of artificial photo-controllable building blocks into known biologically active peptides by replacing their natural building blocks – the amino acid residues. Such a modification would provide photocontrolled peptidomimetics which can reversibly change their structure between two different photo-forms upon irradiation with light of different wavelength. The participating parties possess general know-how for design of the peptidomimetics which can exist in two photo-forms, biologically active and inactive ones, reversibly interconvertible by light of different wavelength. This opens a possibility to convert inactive peptidomimetics to active compounds by irradiation with physiologically benign light directly in tissues with very high spatiotemporal precision and can be a fundamental basis of new therapeutic strategies. The research staff exchange and other activities planned under the Project will be dedicated to accomplish four complementary work packages:
-) carrying out pharmacokinetic and toxicity studies of the photocontrolled peptidomimetics synthesized by the parties previously;
-) evaluation of novel photocontrolled building block chemotypes for their compatibility with peptides;
-) creation of new photocontrolled peptidomimetics, especially based on the novel building blocks and the know-how developed by the parties (e.g. using “stapled peptides” technology);
-) multidisciplinary training of the researchers whose future work will be aimed at further development of the most advanced photocontrolled peptidomimetics as drugs suitable for photodynamic therapy.
3. Developing new therapies for Batten disease, www.batcure.eu
Acronym: BATcure, Contract number 666918
Funding scheme: Research and innovation action
Implementation period: 01.01.2016. – 31.12.2018.
Costs for Latvian partner: 399 625 EUR
Project coordinator: University College London (UK),
Project partners: AcureOmics AB (Sweden), Latvian Institute of Organic Synthesis (Latvia), Cardiff University, (UK), Fondazione Telethon (Italy), Medical Center Hamburg-Eppendorf (Germany), Pronexus Analytical AB (Sweden), The Manchester Metropolitan University (UK), The Royal Veterinary College (UK), University of Salamanca (Spain), Orphazyme APS (Denmark), King’s College London (UK),
Acondicionamiento Tarrasense Associacion (Spain), Batten Diseases Family Association (UK).
Summary
The goal of BATCure is to advance the development of new therapeutic options for a group of rare lysosomal diseases – neuronal ceroid lipofuscinoses (NCL) or Batten disease. There are > thousand affected across Europe, with a combined incidence of c.1:100 000. The NCLs are devastating and debilitating genetic disorders that mainly affect children, who suffer progressive dementia and motor decline, visual failure and epilepsy, leading to a long period of complete dependence on others, and eventually a premature death. Existing palliative treatment can reduce, but does not eliminate, the burden of seizures and the progressively worsening effects on the whole body due to decreasing CNS influence and control. There are no curative treatments in the clinic for any type of NCL. BATCure will follow a novel integrated strategy to identify specific gene and small molecule treatments for three genetic types of Batten disease that include the most prevalent world-wide, juvenile CLN3 disease, and in southern and mediterranean Europe, CLN6 and CLN7 diseases.
To develop new therapies for these 3 types of Batten disease, BATCure will:
- Create new models, tools and technologies for developing and testing therapies,
- Further delineate disease biology and gene function to identify new therapeutic target pathways utilising yeast and pluripotent stem cell models,
- Identify biochemical therapeutic target pathways, facilitate effective evaluation of preclinical therapies and improve diagnostics,
- Extend a comprehensive natural history beyond the brain to include cardiology, the spinal cord, PNS, psychiatric and metabolic changes,
- Identify new and repurpose existing small molecule therapy,
- Triage new compound treatments in zebrafish, a high-throughput small vertebrate model,
- Deliver and monitor new treatments using mouse models,
- Provide a novel mechanism to involve patients and their families to inform and fully contribute to therapy development and prepare for clinical trials.
4. Baltic Biomaterials Centre of Excellence.
Acronym: BBCE, (under contract negotiations)
Funding scheme: H2020-WIDESPREAD-04-2017-TeamingPhase1
Implementation period: 01.09.2017. – 31.08.2018.
Costs for Latvian partner: 56 000 EUR
Project coordinator: Riga Technical University,
Project partners: AO-Forschungsinstitut Davos (Switzerland), Friedrich-Alexander-
Universität Erlangen Nürnberg (Germany), Latvian Institute of Organic Synthesis,
Riga Stradins University.
Summary
The Rudolfs Cimdins Riga Biomaterials Innovations and Development Centre (RBIDC) is a part of Riga Technical University, Latvia (RTU). The RTU RBIDC research team is composed of chemists, chemical engineers and materials scientists. RTU RBIDC scientists are working on well-defined materials science research areas for bone tissue replacement and regeneration. There has been a long lasting cooperation between RTU RBIDC and the Latvian Institute of Organic Synthesis (LIOS) on investigations of biomaterials developed in RTU RBIDC. LIOS has vast experience in preclinical testing of biological/pharmacological activity in in vitro and in vivo systems. Biomaterials developed at RTU RBIDC, in cooperation with clinicians from the Riga Stradins University, Latvia (RSU), have been tested in clinical practice in more than 400 patient cases. RTU RBIDC research fields and scientific capacity will be the core for establishing a new Baltic Biomaterials Centre of Excellence (BBCE) and by adding the crucial experience of RSU and LIOS research fields, full-cycle development of biomaterials will be covered and infrastructure, to create critical mass and excel at specific field and create spill-over effects between different fields. Within the formation of critical mass in research and development, also the cooperation between industry and research organisations will be encouraged, leading to technology transfer and delivery of new products in the market. Hence BBCE project´s main objective is to establish a joint Baltic Biomaterials Centre of Excellence for advanced biomaterials development based on the long-term strategic cooperation between AO Research Institute Davos, Switzerland and Friedrich-Alexander University of Erlangen-Nuremberg, Germany on the one hand and RTU RBIDC, LIOS and RSU on the other hand.
5. Development of high-field DNP-enhanced MAS NMR techniques for structure
determination of viral capsids.
Acronym: virus-DNP-NMR, Contract number 661175
Funding scheme: MSCA-IF-EF Marie Skłodowska-Curie Individual Fellowships
Implementation period: 01.09.2015. – 31.08.2017.
Project coordinator: Centre de RMN à Très Hauts Champs, Ecole Normale Supérieure
de Lyon, CNRS (France), the InnovaBalt strategic partner
Fellow: Dr.Kristaps Jaudzems, Latvian Institute of Organic Synthesis
Summary
The atomic-level characterization of large viral particles is one of the greatest challenges of modern structural biology, as well as a fundamental step for the design of effective antiviral treatments. In viruses, the viral genome (double- or single-stranded RNA or DNA) is associated to multiple copies of a capsid protein, forming predominantly icosahedral or helical architectures. These complex superstructures are often studied by X-ray crystallography and electron microscopy (EM). However, only information at low resolution is usually available from EM, and extended and flexible architectures do not provide single crystals amenable to diffraction studies. Over the last years, solid-state NMR (ssNMR) has developed into a powerful structural tool for studying structure and dynamics of solid biological samples at atomic resolution and is now uniquely positioned to complement diffraction-based techniques for the characterization of large functional assemblies.
However, proteins of large size or that are available in limited amounts are still inaccessible to site-specific NMR studies. Exploiting a unique equipment available in the host institution, the project aims to remove the current bottlenecks and develop improved dynamic nuclear polarization (DNP)-enhanced ssNMR methodology to push forward the limits of applicability of this technique to macromolecular assemblies, opening new avenues to ssNMR in structural biology. Innovative experimental approaches will be developed to overcome the resolution barriers that currently limit the application of high-field DNP, and new spectroscopic tools will be introduced to allow the structure determination of biomolecules under DNP conditions. The effectiveness and versatility of the newly developed methods will be tested on two viral nucleocapsids of different architectures, the icosahedral capsid of non-tailed bacteriophage AP205 and the filamentous, helical nucleocapsid of Measles virus.
EUROSTARS-2 project
6. Super Biased Ligands for Treatment of Type II Diabetes, https://www.eurostars-eureka.eu/project/id/10635
Acronym: SUBERB, Contract number 10635
Implementation period: 01.09.2016. – 31.08.2019.
Costs for Latvian partner: 209 995 Euro
Project coordinator: Atrogi AB (Sweden)
Project partners: Maastricht University (The Netherlands), Stockholm University
(Sweden), Latvian Institute of Organic Synthesis
Summary
Type-2 diabetes is spreading faster than any other disease in the world. In just twenty-five years, the number of people with diabetes has exploded from 30 million people (1985) to 347 million (2012), with recent figures (2016) up to 415 million, and estimated to reach considerably above 500 million people within the next ten years. The largest increase comes from populations in China, India and the Middle East establishing this disease as a global problem. Consortium of project would like to meet this challenge and exceed or complement the current treatment options in todays multi-billion Euro diabetes market. SUBERB addresses this challenge by delivery of a super biased compound for the treatment of type 2 diabetes. This compound through a novel, insulin independent signaling pathway will stimulate glucose uptake in peripheral tissues In this project it is planned to optimize structure of investigated compounds to obtain a prenomination candidate drug (preCD) that can be advanced towards clinical trials, and ultimately, to the large diabetes market. The goal is to deliver at least one compound that meets the standards of a preCD. The compound(s) will be protected by one or more patent applications covering the compound(s) per se and their use in the treatment of type 2 diabetes.
ERA-NET projects
7. Neuroinflammatory mechanisms of chronic neurodegeneration and cognitive decline
following traumatic brain injury, http://www.neuron-eranet.org/_media/Plesnila.pdf
Acronym: CnsAflame
Call: ERA-NET NEURON JTC2014 “Neuroinflammation”
Implementation period: 01.04.2016. – 31.03.2019.
Costs for Latvian partner: 209 990 EUR
Project coordinator: Ludwig-Maximilians University, Institute for Stroke and Dementia, Munich (Germany)
Project partners: University of Bordeaux (France), Latvian Institute of Organic
Synthesis, Uppsala University Hospital, Uppsala (Sweden), The Hebrew University
(Israel), University Hospital Würzburg (Germany).
Summary
Traumatic brain injury (TBI) is the leading cause of disability and death in Europe among young adults and children and an increasing problem in the elderly. While the acute mortality of TBI was reduced in recent years due to improved emergency and hospital care, it has become evident that surviving patients often develop progressive brain atrophy and dementia (chronic TBI) of unknown origin resulting is significant morbidity. Recent animal and human studies suggest that chronic TBI might be accompanied by neuroinflammation. The hypothesis of the current application is that acute TBI triggers a chronic neuroinflammatory response which causes progressive post-traumatic neurodegeneration, cognitive decline and dementia. The scientific aim of the current project is therefore to characterize and understand long-lasting neuroinflammatory changes occurring after TBI and to use this knowledge for developing novel therapeutic strategies which may protect the brain from chronic post-traumatic atrophy and functional decline.
In order to achieve this overall goal, CnsAflame project brought together six internationally competitive research groups with unique experience in TBI and neuroinflammation research and will use state-of-the-art technology (tissue clearing and 3D imaging by light-sheet microscopy, ultra-high field 17.6 T MRI, 2-photon microscopy, 3T PET/MRI) to investigate post-traumatic neuroinflammation in animal models of TBI and in TBI patients. Thereby a unique translational research platform will be created which has the means and the potential to generate novel therapeutic concepts for patients suffering from chronic TBI.
8. Screening and developing of a novel family of natural and synthetic HIV
Integrase inhibitors which do not interfere with V(D)J recombination
Acronym: INinRAGI
Call: ERA-NET HIVERA JTC2014 “European Research Projects on HIV/AIDS”
Implementation period: 01.09.2015. – 31.08.2018
Costs for Latvian partner: 150 000 EUR
Project coordinator: Clinical Hospital Colentina (Romania)
Project partners: University of Szeged (Hungary), Institute of Biochemistry of The Romanian Academy, (Romania), Latvian Institute of Organic Synthesis, National Center for Epidemiology (Hungary)
Summary
After birth newborn infants from HIV infected mothers have to be subjected to prophylactic treatment to prevent viral infection. HIV Integrase(IN) is the enzyme that mediates the viral genome integration into the host cells chromosomes and its catalytic prevention represents a major way to stop the viral infection. Despite its major clinical advantages the treatment with IN inhibitors(INi) in newborns induces a paradoxical situation. Because HIV-IN resembles in its structure and reaction mechanism to RAG1 protein, which assembles the lymphocytes antigen receptors, INi medication interferes with the ability of treated patients to develop a normal immune response. INinRAGI project is targeted to solve the major drawback of INi treatment that it cannot be addressed to newborns exposed to high risk acquiring HIV-1 infections. The major goal of project is to test new HIV specific Integrase inhibitory compounds which do not interfere with RAG somatic recombination. Project proposes to develop rapid, low cost, efficient FRET screening assays. With them will be HTP screen first a library of natural compounds (NP) of herbal origin. Informed by the best selected NPs we will in silico design and synthesize a derivatized set of HIV-INi compounds which will be again screened in vitro for dual HIV Integrase inhibition and RAG noninterference effects. The uniquely discovered lead compounds will also be tested in immune B cell progression assays and for their antiretroviral potency on HIV infected T cells.
9. Study of the new post-replicational modification of DNA by Poly(ADP-ribose)
polymerases and its implication for anticancer therapy
Acronyme: DNA PARYLATION
Call: ERA-NET RUS-PLUS JTC2015 “Joint call on Science and Technology” Implementation period: 01.01.2016. – 31.07.2018.
Costs for Latvian partner: 60 000 EUR
Project coordinator: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk (Russia)
Project partners: Centre National de la Recherche Scientifique, UMR 8200 Stabilité génétique et oncogenèse, Villejuif (France), Latvian Institute of Organic Synthesis.
Summary
The aim of the present study is to obtain new insights into the molecular mechanisms of PARPs mediated regulation of DNA repair, DNA transcription, chromatin dynamics and cell death. Our preliminary studies suggest that the Poly(ADP-ribose) (PAR) polymerases, PARP1 and PARP2 can covalently modify not only acceptor proteins but also DNA termini at strand breaks by transferring ADP-ribose units to 3'-hydroxyl and/or 3'-phosphate at the end of a gap and to 3'-hydroxyl of a nucleotide at the end of a double-strand break.
Project proposes to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.
The project is structured of four complementary tasks:
- Examination whether the PARylated termini of DNA strand breaks block DNA replication fork progression and inhibit the toxic non-homologous end-joining.
- Identification of PAR-DNA Adducts in living cells using biochemical and biophysical approaches.
- Biochemical characterization of substrate specificities of the members of PARP protein family.
- Development of new PARP and PARG inhibitors (directed by Latvian partner).
The major objectives of this task are to clarify the role of PARP and PARG proteins in DNA repair and to find new inhibition strategies. Recent results of Latvian team indicate that some derivatives of 1,4-dihydropyridines (1,4-DHPs), possessing anti-mutagenic activity can interact directly with DNA and, unexpectedly, with PARP1. This opens a possibility for search of novel inhibitors of PARP1 among 1,4-DHPs. Here, we propose to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.
10. Innovative Nanopharmaceuticals: Targeting Breast Cancer Stem Cells by a Novel
Combination of Epigenetic and Anticancer Drugs with Gene Therapy.
Acronyme: INNOCENT
Call: ERA-NET EuroNanoMed-II 2016
Implementation period: 01.04.2017. – 31.03.2020.
Costs for Latvian partner: 209 770 EUR
Project coordinator: Biomedical Research Centre, Slovak Academy of Sciences (Slovakia)
Project partners: Latvian Institute of Organic Synthesis, Hospital Universitari Vall d’Hebron (Spain), University of Bergen (Norway), Norwegian Institute for Air Research (Norway), eNIOS , private company (Greece).
Summary
The last decade has seen a flourishing in the study of the properties of nanoparticles for medical applications. The next generation of nanopharmaceuticals combine a series of advances which enable the creation of multimodal/multifunctional nanodrugs that may contain anti-tumour agents, targeting ligands designed to home in on malignancies together with imaging agents to light up even the earliest stage of cancers. The nanotechnology in combination with conventional chemotherapy, gene therapy and epigenetics opens the door to novel therapeutical approaches. The aim of the INNOCENT project is to develop innovative multifunctional nanopharmaceuticals to overcome the low efficacy and frequent relapses in breast cancer (BC) treatment, with emphasis on cancer stem cells (CSCs). The proposed multimodal COMBOBOMB, brilliantly integrates the diagnostic and therapeutic functions within a single nanostructure. The COMBOBOMB harbours four major components: 1) a selective targeting moiety (chitosan-targeted CD44); 2) a diagnostic imaging aid for localization of the malignant tumour and its micro- or macrometastases (inorganic nanocrystals); 3) a cytotoxic drug (doxorubicin), and 4) a chemosensitising agent (decitabine, DAC along with DAC-activating enzyme) utilising gene therapy and epigenetic approaches. The inorganic nanocrystals entrapped in the nanocarrier will allow real time non-invasive imaging of the COMBOBOMB biodistribution and accumulation at the tumour site, and will allow the monitoring of patients` response to treatment. The rationally designed multifunctional nanodrug will offer new possibilities of penetration into CSC niches and open new horizons for treatment of tumour cells in bulk and CSCs. The COMBOBOMB has the potential to be used also as neoadjuvant therapy, to decrease the probability of tumour cell dissemination (mainly via the CSC subpopulation). Moreover, this multifunctional nanotherapeutical could increase the efficacy of radiotherapy by ehancing radiosensitization of tumour tissue. The COMBOBOMB represents a new generation of nanomedicine with enhanced potential for both therapeutic treatment and decreased recurrence of BC, with potentially high impact on survival and quality of life of BC patients. This multidisciplinary, highly collaborative bench-to-bedside approach will provide both economic impact and added value for public health.
11. Time dependent Remote Alterations after Injury to the Nervous System
Acronyme: TRAINS
Call: ERA-NET NEURON JTC2016
Implementation period: 01.06.2017. – 31.05.2020.
Costs for Latvian partner: 209 000 EUR
Project coordinator: CNRS - Université de Bordeaux (France),
Project partners: University of Munich (Germany), Weizmann Institute of Science (Israel), UMR1141 Inserm - Paris Diderot University (France), Medical University of Lodz (Poland), Latvian Institute of Organic Synthesis.
Summary
Injury to the brain or the spinal cord results in long term functional deficits in affected patients which mainly affect sensation and motor function. Traditionally it was believed that these impairments are solely caused by the initial local brain damage. However, an increasing body of evidence now indicates that in addition to the acute local changes also distant areas of the brain connected to the primarily injured area are also critically involved in this process.
The main hypothesis underlying this project is that sensori-motor dysfunction (smD) following a focal injury to the central nervous system is associated with remote alterations occurring distant from the primary lesion site (remote brain injury, remBI). Since the mechanisms of remBI are largely unknown, the aim of the current application is to understand how, where, and when remBI occurs after traumatic brain (TBI) and spinal cord injury (SCI) and to use this knowledge for the development of novel therapeutic strategies for patients suffering from long-term dysfunctions after CNS injury. For this purpose we put together a consortium of excellence with internationally recognized experts in the field of CNS injury with surpassing expertise in the investigation of the brain and the spinal cord. This consortium will study remBI in neonate, juvenile, adult and aged rodent models of TBI and SCI by using state-of-the-art and newly developed in vivo (small animal, MRI, 2-photon microscopy, bio-orthogonal chemical reporter) and ex vivo (viral tracing, tissue clearing) technologies. The first work package (WP1) will investigate the temporal and spatial profile of neuronal reorganizations and inflammatory processes for up to 6 months after injury. Brain and spinal cord tissue will be studied and correlated with changes in smD. The WP2 will decipher the key cellular and molecular mechanisms with a focus on the neuronal connectivity (dendrites, axons, spines and synapses), immune-glial cell interactions (monocytes, microglia, astrocytes), and vascular changes (endothelial cells, pericytes, astrocytes). Finally, WP3 will identify potential treatments for smD: 1) stabilization of glial and neuronal microtubules, 2) adaptive transfer of monocytes, and 3) inhibition of JNK pathway. These studies will be performed using a pre-clinical multi-center trial design. Newly developed in vivo and ex vivo CNS imaging technologies together with state-of-the art treatment will be used. This project will establish a long-term collaborative network of excellence and provide a future basis for the design of novel therapeutic strategies, which will outlive the current funding period.
12. Engineering and functionalization of delivery system with Pelargonium sidoides
biologically active substance on inflamed periodontal surface area.
Acronyme: PELARGODONT
Call: M-ERA.NET JTC2016
Implementation period: 01.06.2017. – 31.05.2020.
Costs for Latvian partner: 45 650 EUR
Project coordinator: Lithuanian University of Health Sciences (Lithuania)
Project partners: Centre of Polymer and Carbon Materials Polish Academy of Sciences (Poland), Latvian Institute of Organic Synthesis, Jagiellonian University in Krakow (Poland), Riga Stradins University (Latvia), Università Piemonte Orientale (Italy), UAB Ferentis (Lithuania).
There are many patients in dental practice who have some form of periodontal disease. Periodontal diseases range from simple gum inflammation to serious disease that results in major damage to the soft tissue and bone that support the teeth. In the worst cases, teeth are lost. Common strategy for treatment of periodontitis treatment include use of antibiotics and synthetic antiseptics that is accompanied by systemic side effects and increased bacterial resistance. Such strategy is not suitable for prolonged or repeatable treatment and fails to stop disease remission and further progression. This creates a demand for local delivery devices with multiple antibacterials of mild action. The aim of this project is to engineer and functionalize a biodegradable mucoadhesive drug delivery system of local action with natural active substance for periodontitis treatment. To avoid negative impact of antibiotics and synthetic antiseptics, a set of natural biologically active compounds from Pelargonium sidoides is chosen as an alternative prevention and treatment option. The system will be designed to release optimized levels of multiple antibacterials from Pelargonium sidoides root extract in the disease - affected area for a sustained period of time aiming for both ease of use and high patient acceptance. The system will be designed from biodegradable polymer- peptide carriers.
The project will start from a preformulated concept (TRL 2) for the delivery system of biodegradable carrier and antimicrobial active substance. During the 24 month research the concept will be developed to the form of prototype (TRL 5) and demonstrated as an active medical device in a clinical trial. Technology will be validated and fabrication process optimized together with UAB Ferentis, a research intensive biotechnology company involved in the development of biomaterials for in vitro cell cultures, tissue engineering and regenerative medicine applications. The implementation of the project will consist of three main workblocks: 1) investigation of the protective and antibacterial effects of the active substances in vitro studies and investigation of delivery material, 2)construction and development of a local delivery device prototype, and 3) local delivery device prototype testing in a clinical trial.
Scientific research performed will prepare the ground for new methodology to design interfaces between natural biologically active substances in a biodegradable carrier and periodontal inflamed surface area. The project will deliver an innovative product that will help avoid or delay surgical treatment, and prevent side effects including hypersensitivity, gastrointestinal intolerance and development of bacterial resistance.
Projects of mutual fund Taiwan – Latvia – Lithuania
12. Design of anticancer pharmaceutical compounds using structure and energetics of
lead – target interactions
Implementation period: 01.04.2016. – 31.03.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: National Central University (Taiwan), Latvian Institute of Organic
Synthesis, Vilnius University (Lithuania)
Summary
Rational drug design begins with the phase of discovering lead compounds that strongly interact with target proteins and could be modified, improved and developed into pharmaceuticals. Epigenetic targets are currently considered as one of the most exciting biological target areas to be tackled with drugs against numerous diseases.
Epigenetic mechanisms are inheritable factors that regulate genetic expression and chromatin architecture without changing the DNA sequence. These factors are DNA methylation, histones modifications (methylation, acetylation and phosphorylation), activity of various non histones proteins that bind to the DNA and small regulatory RNAs. Epigenetic enzymes regulate histones and DNA changes by these simple chemical modifications and determine whether genes are turned on or off, and deregulation of the processes plays a central role in several diseases.
Numerous studies have shown the efficacy of epigenetic drugs in hematologic malignancies and several more are showing that epigenetic drugs when used in combination with anti-cancer drugs are driving solid tumor treatment. According to the Structural Genomics Consortium, there are 377 known epigenetic targets. But epigenetics has so far yielded only four approved drugs.
The three research teams of this project have combined their efforts to improve the knowledge of protein – drug recognition and to make compounds that would be proposed to develop as drugs primarily against cancer. All three teams have significant experience and continue to use the target-based drug discovery approach. Protein targets will be a part of the epigenetic proteins, mostly metalloenzymes containing zinc in their active site. Metalloenzymes are widely distributed in human body and their loss of activity or misregulation causes numerous diseases.
Choosing similar target proteins helps by grouping the compounds to a limited set of pharmacophore groups that would bind to a particular set of targets. For example, aromatic primary sulfonamides are widely known to tightly and specifically bind and inhibit carbonic anhydrases (CAs). Similarly, hydroxamic acid-containing compounds recognize and bind one group of zinc-containing histone deacetylases (HDACs), a class of epigenetically modifying enzymes.
The consortium proposes to design, synthesize new eventually active compounds and to develop methodology for their activity screening by calorimetry methods. The mechanisms of action would be tested by the X-ray structure studies to develop further more active compounds. All the planned activities logistically follow each other and the new results may optimize the process of development of leading structures.
13. Synthesis and studies of high-triplet-energy materials for blue OLEDs
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: Graduate Institute of Photonics and Optoelectronics (Taiwan),
Latvian Institute of Organic Synthesis, Kaunas University of Technology (Lithuania)
Summary
During the last decades all colour light-emiting diodes (OLEDs) have evolved into commercial applications such as flat-panel low-weight displays or sources of solid state lighting. Today, the efficiency of OLEDs is at product-relevant levels for all colours excepting blue. Therefore, high-efficient blue OLEDs with industry-standard device lifetimes have to be realized to fully open the potential of OLEDs. Recently blue thermally activated delayed fluorescence (TADF) and phosphorescence emitters (having values of triplet levels higher than 2,7 eV) were developed application of which can allow to achieve the internal quantum efficiency of blue OLEDS close to 100 %.
Synthesis and studies of high-triplet energy charge-transporting materials are the main objectives of this joint project. The tasks of the project include development efficiency organic semiconductor materials with high triplet-energy values for new-generation blue OLEDs including the theoretical modelling and designing of charge-transporting materials, their synthesis and characterization of charge transportproperties in solid state, detailed investigation of transport properties in solid state, detailed investigation of transport mechanisms and correlation with molecular structures and morphology etc., fabrication and characterization of light-emitting devices using the most promising materials. OLEDs with the maximum external quantum efficiency higher than 15% will be fabricated and characterized. The turn on voltage of the OLEDs will be lower than 3,5 V. The maximum brightness higher than 5000 cd/m2 will be reached that will unclose the practical applications of blue OLEDs.
14. Understanding prion peptide fibril-induced aggregation of prion protein.
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: Institute of Biological Chemistry, Academia Sinica (Taiwan),
Latvian Institute of Organic Synthesis, Vilnius University (Lithuania).
Summary
Prion-like spreading may be employed in a number of fatal neurodegenerative disorders, including such as Alzheimer’s and Parkinson’s diseases. Understanding all possible mechanisms of such spreading would be a big step towards curing these diseases.
Recent work showed that prion protein aggregation can be induced by short peptides. It seems that either structure of peptide-induced prion protein aggregation (piPrP) or the mechanism of its formation is different from the current knowledge in the field. Project is targeted to the comprehensive study of piPrP structure, starting from low resolution methods as Fourier transform infrared (FTIR) spectrometry and proteinase K resistance studies, but focusing on medium and high resolution methods in hydrogen exchange mass spectrometry, and solid state nuclear magnetic resonance spectroscopy. High resolution structure will lead to the ultimate goal of project – getting deeper into mechanisms of prion-like self-replication of amyloid fibrils.
15. Nanoarchitectonics of Metal-Organic Frameworks (MOFs): Design, Dielectric
Property, and Organic Catalysis
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: National Taiwan University (Taiwan), Latvian Institute of Organic
Synthesis, Vilnius University (Lithuania)
Summary
Project is focused on the design and synthesis of novel metal organic frameworks (MOFs), and the application of this class of materials on catalysis and membrane separations. MOFs possess highly ordered nanopores, good tenability for interior surface properties, and high porosity. These materials have drawn a great research attention in the past decade due to their potentials on catalysis, adsorption and electrophotonics. This work is aimed at two specific application fields, membrane separation and catalytic asymmetric reactions. Consortium will employ the concept of molecular self-assembly on designing and tuning the multiscale microstructure for prevaporation and asymmetric reactions. The self-assembly mechanisms of MOF materials will be studied and then new MOFs exclusively for the specific catalytic reactions and the separation systems will be synthesized. Subsequently, the cutting-edge characterisation techniques and homemade instruments will be applied to perform a comprehensive structural and functional characterisation. This project is expected to create high impact on both nanomaterials and catalytic reactions.
EEA and NORWAY Grants
16. Benefits and detrimental effects of sequence variants of Amyloid-β: towards the use
of small peptides for aggregate dissolution therapy in dementia.
Implementation period: 01.05.2015. – 30.04.2017.
Costs for Latvian partner: 166 711 EUR
Project coordinator: Latvian Institute of Organic Synthesis
Project partners: University of Latvia, University of Oslo (Norway)
Summary
The overall goal of this project is to develop the new strategy for the treatment of the Alzheimer disease (AD) and to enhance research-based knowledge in Latvia through a long term collaboration between project partners. The research group of Latvian Institute of Organic Synthesis will provide expertise in structural analyses to start an iterative set of experiments. The University of Oslo will provide knowledge and expertise in the field of disease models and analyses. The researchers of University of Latvia will have access to world-wide unique mouse models, and are skilled in the performance of behavioural and cognitive tests. The outcome from this Latvian-Norwegian research cooperation project will be the identification of neuroprotective properties of short N-terminal peptides of Aβ for their propensity to remove toxic Aβ peptide deposits and improve cognitive functions which may introduce new options in AD therapy.
17. Image-guided cancer gene therapy in combination with advanced chemotherapeutics
Implementation period: 01.05.2015. – 30.04.2017.
Costs for Latvian partner: 140 000 EUR
Project coordinator: Latvian Biomedical Research and Study centre
Project partners: Latvian Institute of Organic Synthesis, University of Oslo Hospital
(Norway)
Project overall objective is to develop an efficient strategy for cancer treatment based on application of image-guided targeted chemotherapeutics in combination with viral gene therapy vectors. Project presents a new collaborative research initiative within the field of cancer therapy. Project consortium proposes to apply novel alphaviral vectors encoding cytokines, which able to stimulate tumor-associated macrophage (TAM) infiltration into the tumor and induction of pro-inflammatory microenvironment to block tumor recovery after chemotherapy. Several mouse models of breast cancer, melanoma and xenograft model of human lung carcinoma will be treated with chemical compounds with significant anti-proliferative properties followed by the application of alphaviral vectors. The outcomes of treatment will be monitored using advanced imaging technologies including bioluminescent and fluorescent imaging. The molecular mechanism underlying the alphaviral tumor tropism will be investigated in details using a comparative proteome analysis of cancer cells susceptible and unsuceptible to alphaviral invection. Therefore, the aim of this study is to develop an efficient strategy for cancer treatment based on an application of image-guided targeted chemotherapeutics in combination with gene therapy vectors. Special attention will be paid to training of young researchers in cutting-edge imaging techniques, advanced immunological methods and mass spectrometry approaches. The research credibility is justified by the broad and complementary expertise of participating groups from three institutions Latvian Institute of Organic Synthesis, Latvian Biomedical Research and Study Centre and Oslo University Hospital.
Ukraine – Latvia collaboration project
18. Elaboration of fluorine containing amphiphilic heterocycles as delivery systems and
evaluation of their self-assembling properties with perspective as new materials for
use in biomedicine.
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 40 000 EUR
Project partners: Latvian Institute of Organic Synthesis, Institute of Organic
Chemistry, National Academy of Science of Ukraine.
Summary
The aim of this project is the elaboration of new kinds of nanoparticles formed by cationic lipids with fluorine containing substituents as the potential transmembrane delivery agents in cooperation experience between research groups from Latvia and Ukraine. This aim will be achieved by the implementation of the following objectives:
1) Synthesis of the original fluorous containing building blocks:
alcohols, esters of acetoacetic acid and 3-aminobut-2-enoic acid esters, benzaldehydes;
2) Design and synthesis of the original delivery systems with improved properties:
construction at 3,5-positions of 1,4-DHP cycle AlkH or AlkF containing esters,
introduction of various fluorine containing phenyl substituents at the position 4 of
1,4-DHP cycle,
exchange of H to F atom at the position 4 of DHP cycle,
variations of F-containing pyridines at the positions 2,6 of DHP cycle.
3) Characterisation of self-assembling properties of new fluorine containing delivery
systems with improving properties.
4) Dissemination of the results in SCI journals and international conferences at both countries.
Implementation of this project will give a contribution for the achieving the aims of the strategy of nanotechnology which is one of the six Key Enabling Technologies and has a significant impact on many different medicinal developments in the three main areas: Therapeutics, Diagnostics/Imaging and Regenerative Medicine.
Osmosis programme (collaboration with France)
19. Multivalent Inhibitors of Bacterial Carbonic Anhydrases: Molecular Innovation in the Field of Anti-infective Agents
Implementation period: 01.03.2016. – 28.02.2018.
Costs for Latvian partner: 4000 EUR
Project partners: Latvian Institute of Organic Synthesis, Université de Montpellier
(France).
Summary
The main objective of project is to develop long-lasting collaboration between research groups of the LIOS and Université de Montpellier (France).
The scientific aim of project is to develop homotopic and heterotopic multivalent systems by molecular engineering, starting from cyclopeptidic scaffold, in order to study the importance of the multivalent effect on the activity and selectivity of inhibition of bacterial carbonic anhydrases.The project is based on the complementary skills of both groups:
The French team has proven expertise in the development of modulators of activity of human and bacterial carbonic anhydrases. In the development of innovative synthetic methodologies for the effective preparation of bioconjugates multifunctionalized by a "click" self-assembly approach using biocompatible and chemoselective ligations. We have already prepared multivalent nanoconstructions based on functionalized cyclic peptides that have proven to be very effective for the recognition of lectins or integrins. A multifunctional compound combining integrin recognition properties and fluorescence imaging was later developed and successfully applied to the in vivo tumor imaging for assisting surgery. The LIOS team has proven expertise in the design and synthesis of highly potent and isoform selective inhibitors of human carbonic anhydrases. Latvian team has developed reliable synthetic methodology for the synthesis of coumarin bioisosteres – 1,2-benzoxathiine 2,2-dioxide or so called sulfocoumarins. The LIOS researchers also have developed several methodologies for the derivatization of sulfocoumarins, including C-H activation and click chemistry. It has been demonstrated that sulfocoumarins are highly selective inhibitors of several human CAs with the inhibition activity in low nanomolar range.
During the project will be implemented mutual visits for the development of further joint research projects.
Potential Impact:
The implementation of the Action Plan of InnovaBalt was carried out by the coherent set of measures:
-) exchange of know-how and experience with EU partnering organizations;
-) recruitment of experienced researchers and technical staff;
-) upgrading of research infrastructure;
-) elaboration of a strategic IP development plan for IP management
and innovation capability building;
-) dissemination of knowledge on health and increasing the visibility of InnovaBalt activities at regional, national and EU levels.
Expected impacts achieved during the implementation of the InnovaBalt project are listed below.
1. Better integration of the LIOS in the European Research Area (long lasting partnerships) was reached via
- ) collaborations and exchange of experience with 50 European research institutions in research, IPR, technology transfer and project management issues (outgoing and incoming visits);
-) organization of 12 transnational events, including the workshops on preparation of proposals for Horizon2020 proposal preparation
-) increased visibility of LIOS by communication and dissemination activities.
2. Upgraded RTD capacity and capability (human potential, training of research staff, scientific equipment) was gained by
- ) exchange of know-how and experience via international two-way secondments of experienced scientists and young scientists between the LIOS and leading scientific institutions in the ERA, provided access to complementary equipment resulting in improvement and development of new skills of the LIOS staff,
-) recruitment of experienced researchers (with expertise in drug discovery and preclinical development programmes; bioinformatics and molecular modelling; modern synthetic chemistry with a special emphasis to the development of methods for pharmaceutical industry),
-) reintegration of experienced researchers, former co-workers of LIOS, from abroad;
-) renewal of equipment which is essential for the advanced innovative drug development,
-) systematic training of early-stage and experienced researchers on research, IPR, technology transfer and project management issues .
3. Improved research capacity for effective contribution to regional economic and social development was achieved by
-) increased availability of new LIOS infrastructure facilities to researchers from other regional research centres,
-) organization of regional seminars, workshops, conferences on research, IPR, technology transfer and project management issues,
4. Improvement of participation of LIOS in Horizon 2020 and other important European programmes was reached via
-) improved skills for competitive proposal preparation and successful management by organization of training courses,
-) increased visibility of the LIOS by participation in conferences, information days and brokerage events,
-) organization of targeted proposal preparation workshop intended to help with further identification of relevant calls and partners.
5. Improvement of innovation potential in Baltic region was achieved by
- ) recruitment of experienced specialist in IP issues;
- ) staff exchange with for improving of experience of management in IP and technology transfer
- ) elaboration of Strategic Intellectual Property development plan for the LIOS;
-) innovation capacity building through the set of trainings for researchers and SMEs in Baltic region;
-) organization of transnational seminar ”Knowledge to innovation” ;
-) actualization of IPR and technology transfer issues in agendas of transnational conferences;
-) Increased awareness of industry partners about the topicalities in the innovative drug research.
All planned measures of the InnovaBalt project were carried out, and expected results were achieved. The fulfilment of the Action Plan has ensured the further sustainability of the LIOS activities. Collaboration with partnering institutions and competence of recruited researchers has increased the total number of publications. There was an increase in the number of publications in journals with impact factor higher than 4 during the last 4 years (starting from 1 paper in 2012 to 16 papers in 2015). The increase of publications in journals with impact factor higher than 4 is evidenced when looking at the average impact factor of LIOS’s scientists publications per year (a 1.7-fold increase from average impact factor = 1.58 in 2012 to IF=2.69 in 2016). Some researchers already published their scientific work in journals with impact factor higher than 10.
LIOS Researchers have participated in the preparation and submission of 22 proposals for Horizon 2020 calls (01.01.2014.-31.12.2016.). From the submitted proposals 4 are successful (success rate 18 %), 16 are above thresholds (without funding) and just 2 proposals were rated below threshold. Ongoing Horizon 2020 projects in LIOS:
-) BATcure - Developing new therapies for Batten disease (contract Nr.666918 funding for LIOS - 399 625 EUR),
-) PELICO - Peptidomimetics with Photocontrolled Biological Activity (Marie Sklodowska-Curie Research and Innovation Staff Exchange Project, contract number: 690973, funding for LIOS - 103 500 EUR).
-) INTEGRATE Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets (Marie Sklodowska-Curie Innovative Training Network Project, contact number: 642620 , funding for LIOS - 223 577,64 EUR)
-) The implementation of theH2020-WIDESPREAD-04-2017-TeamingPhase1 project BBCE (Proposal: 763721; Baltic Biomaterials Centre of Excellence, funding for LIOS – 56 000 EUR) will start in September 2017.
The LIOS was already accepted to enter into 19 different collaborative research project consortia, generating more than 2 million EUR new funding for LIOS. Short annotations of these projects are presented in the final report S&T foreground. These results have become possible through the InnovaBalt activities that focused on international scientific exchange, and increased the visibility and contacts of the LIOS. These data show that within the ranks of European scientific institutions in the field of drug discovery, biochemistry and medicinal chemistry the LIOS is a well accepted partner for scientific work in international consortia. The LIOS current position in the scientific ecosystem is based strongly on the institute’s very well maintained contacts to other researchers and InnovaBalt has been very helpful in enlarging LIOS’s contacts and reach. The research topics that have been pursued under scientific grants focus on several meta-topics: new antibacterial strategies, strategies against cancer, degenerative diseases of the nervous system and other neurologic defects. These meta-topics link with the most interesting and actually most urgent medical problems of our age. LIOS ability to join and perform within these consortia is based on widespread contacts and networking among the European chemical and pharmacological research community, good research infrastructure, staff of researchers and management.
The LIOS is best characterized by a deeply rooted dualism of its activities: the LIOS successfully combines contract research with basic research and through it gains synergy and added value. Both scientific research and contract research are integral parts of the institute, and they will need to remain there in the future. The LIOS has always been focused on manifesting its research results in patents and other forms of intellectual property. The InnovaBalt gave this approach an additional boost through improving the management of intellectual property and through enhancing awareness for the topic among the scientific employees. By making the whole topic of intellectual property transparent for the scientists, a climate of innovation was created at the institute. The InnovaBalt project contributed to the regional economical development through strengthening tight collaboration with industry and innovative drug discovery projects in the LIOS. The InnovaBalt project activities are expected to have long-term social and economic impacts in relation to transformation of the national economy and growth priorities defined in the Latvian Smart Specialization Strategy, especially in RIS3 area of specialization: 2. Biomedicine, medical technologies, biopharmacy and biotechnologies.
Contract research is a large and stable portion in the LIOS’s funding. The average annual share of 42% in the research budget (years 2013 to 2016) is high among European academic institutions. LIOS is best characterized by a deeply rooted dualism of its activities: LOIS successfully combines contract research with basic research and through it gains synergy and added value. Both scientific research and contract research are integral parts of the institute, and they will need to remain there in the future.
Visibility of the LIOS and dissemination activities.
Increased visibility of LIOS has been reached through the regular participation and exploitation of research results in the international conferences and by the organization of international events in Latvia. Manager of InnovaBalt, Professor Maija Dambrova, presented experience and results of InnovaBalt in 3 European events:
-) the workshop during WIRE 2015 „Week of Innovations regions in Europe”, Riga, 3.06. 2015 (Latvia’s Presidency event),
-) the workshop „Contribution of "Research Potential" (REGPOT) and "Regions of Knowledge" (ROK), the way forward thanks to synergies between EU policies/funds”, Brussels , 07.12.2015.
-) Conference “Bridging the Divide in European Health Research and Innovation”, Brussels, 20.10.2016.
In total 68 activities (info in websites, press releases, TV clips, interviews, articles in press, posters, Cafe scientifique, flyers, virtual tour, video) were carried out.
A widely attended press conference took place in the LIOS on February 28, 2017, the last day of the InnovaBalt project implementation. The Coordinator of project Professor Ivars Kalvins, Manager of project, Professor Maija Dambrova and Director of LIOS Osvalds Pugovics presented results achieved during the InnovaBalt project, recommendations of the external evaluation expert panel and plans for the future development and research strategy of LIOS. The representatives from the strategic partnering institutions: the University of Latvia, Riga Technical University, Riga Stradins University, the Association of Latvian Chemical and Pharmaceutical Industry, briefly informed about the examples of successful cooperation with LIOS in the past and intentions for future. The press conference materials were comprehensively reflected in the mass media: 10 TV plots, 18 radio plots, 4 articles in national newspapers and 42 briefings in internet portals (in total 74 communications).
List of Websites:
www.innovabalt.eu
Virtual tour about OSI www.osi.lv/en
Video: https://www.youtube.com/watch?v=FQEzm4XtE8I&feature=youtu.be
Latvian Institute of Organic Synthesis (LIOS) has finished the implementation of the FP7 project InnovaBalt: Strengthening the research and innovative capacities of the Latvian Institute of Organic Synthesis, the leading Baltic regional centre for drug discovery.
The general goal of this project was to unlock and to develop the existing excellence in the LIOS and to become active player in the ERA (European Research Area). The objectives of the InnovaBalt were achieved through a set of measures:
• exchange of know-how and experience with EU partnering organizations;
• recruitment of experienced researchers and technical staff;
• upgrading of research infrastructure;
• elaboration of a strategic IP development plan for IP management
and innovation capability building;
• dissemination and communication activities, the increasing of visibility of the
InnovaBalt activities at regional, national and EU levels.
The fulfilment of the InnovaBalt objectives were evaluated by external experts to define specific actions for the future sustainability of LIOS.
The main results of InnovaBalt project:
1. During the InnovaBalt collaboration with 50 research institutions was implemented. In total 62 incoming visits of recognized researchers and 76 outgoing visits to partnering organizations were carried out.
2. InnovaBalt project supported recruitment of 12 experienced and 7 post-doctoral researchers. It should be emphasized that 6 of them were Latvian researchers previously working at the leading European research institutions. Recruitment of these researchers decreased brain-drain which was indicated as a threat in the SWOT analysis of LIOS.
3.Researchers involved in the InnovaBalt project activities have published 34 scientific articles in SCI journals.
4. The equipment acquired in the InnovaBalt has been intensively used and upgraded. Equipment includes 7 devices and systems, which will strengthen LIOS infrastructure in nanotechnology, protein crystallography, imaging in living animals in real time, fluorescent spectroscopy and computing.
5. During the InnovaBalt project implementation 12 international events have been organised.
6. LIOS patent portfolio has been updated and strengthened, future strategy developed. IP manager, recruited during the InnovaBalt, continues to be employed by LIOS.
7. Visibility of LIOS has been reached through the regular participation and exploitation of research results in the international conferences and by the organization of international events in Latvia. Manager of the InnovaBalt, Professor Maija Dambrova, presented experience and results of the InnovaBalt project in 3 European-level events:
- the Workshop during WIRE 2015 „Week of Innovations regions in Europe”, Riga, 3.06. 2015 (Latvia’s Presidency event),
- the Workshop „Contribution of "Research Potential" (REGPOT) and "Regions of Knowledge" (ROK), the way forward thanks to synergies between EU policies/funds”, Brussels , 07.12.2015.
- Conference “Bridging the Divide in European Health Research and Innovation”, Brussels, 20.10.2016.
The synergy of the InnovaBalt project with different EU Structural Fund activities has been achieved.
The InnovaBalt project contributed to the regional economical development through strengthening tight collaboration with industry and innovative drug discovery projects in LIOS. The InnovaBalt project activities are expected to have long-term social and economic impacts in relation to transformation of the national economy and growth priorities defined in the Latvian Smart Specialization Strategy, especially in RIS3 area of specialization: 2. biomedicine, medical technologies, biopharmacy and biotechnologies.
Website: www.innovabalt.eu
Virtual tour about OSI: www.osi.lv/en
Video: https://www.youtube.com/watch?v=FQEzm4XtE8I&feature=youtu.be
Project Context and Objectives:
The InnovaBalt was a 4.7 million project supported by the FP7. The FP7 “Research Potential” (REGPOT) Programme was created to unlock and develop existing excellence in the EU’s Convergence regions and Outermost regions, and to help research actors in these regions to become active players in the ERA (European Research Area). The priority was to increase the research potential in these regions and improve their knowledge and technological processes – contributing to the growth, productivity and employment of these regions.
Duration of the InnovaBalt was from 01.09.2013 till 28.02.2017. During the InnovaBalt project period the Action plan based on SWOT analysis of LIOS was implemented. The strategic objective of the InnovaBalt was to strengthen the multidisciplinary research capacities, management of intellectual property as well as human resources in the innovative drug discovery at LIOS.
The short term objectives of the InnovaBalt project were following:
1. To establish and to strengthen the long-lasting scientific collaboration and strategic partnership between LIOS and outstanding research institutions in ERA;
2. To increase the innovation and improving of management of intellectual property through collaboration and attraction of external professionals;
3. To upgrade the research infrastructure at LIOS to promote the capacity for the high level research on innovative drug development;
4. To increase the visibility of LIOS in ERA;
5. To ensure the synergy between research on innovative drug development and end-users (SMEs, industry, clinics, patients’ organizations);
6. To reinforce the strategic development of LIOS to improve the response to socio-economic needs of Baltic region in health area.
The implementation of Action Plan was carried out by the coherent set of measures structured into 8 work packages (WP).
WP1. Exchange of experience and know-how (via international two-way secondments of experienced and young researchers of LIOS with researchers from excellent and complementary European research centres).
Objectives of WP1:
-) to promote the exchange of experience and to know-how,
-) to build the capacity of LIOS researchers by obtaining the necessary knowledge and skills,
-) to strengthen the networking with partner organizations to ensure the long lasting further cooperation.
WP2. Strengthening of the research potential of human resources
Objectives of WP2:
-) to increase the LIOS research capacity and experience in new directions of drug discovery by recruitment of experienced researchers,
-) to increase the international-level transfer process of accumulated knowledge and technologies through the reintegration of experienced researchers from abroad,
-) to increase the research potential of existing laboratories by recruitment of post-doctoral researchers.
WP3. Renewal of research equipment
Objectives of WP3:
-) to acquire a modern equipment and tools necessary for innovative drug development;
-) to upgrade the research equipment of LIOS.
Description of work and role of partners
WP4. Organization of seminars and conferences
Objectives of WP4:
-) to facilitate the knowledge transfer at the national, regional and international levels, to ensure the synergy between research on innovative drug development and end users,
-) to increase the visibility of LIOS by dissemination of the results of LIOS researchers in organic chemistry, medicinal chemistry of heterocycles, structure-activity relationships, experimental chemotherapy and pharmacology to the international scientific community. -) to strengthen the long-lasting scientific collaboration between LIOS and partnering organisations in ERA.
WP5. Improving the management of Intellectual Property and enhancement of innovation potential
Objectives of WP5:
-) to increase the innovation potential at the national, regional and trans/international levels to give contribution to the economic growth in the area of innovative medicine,
-) to improve knowledge of researchers (both early stage and experienced) and stakeholders from the pharmaceutical industry on Intellectual property rights (IPR), their management and technology transfer issues,
-) to strengthen the long-lasting collaboration between LIOS and end-users (industry) to ensure the technology transfer for the innovative drug development targeted to the challenges in health area.
WP6. Dissemination and promotional activities
Objectives of WP6:
-) to promote the InnovaBalt project within the scientific community of Europe to ensure the long lasting integration of LIOS in ERA,
-) to disseminate the information on advanced innovative medicine development to the industry sector and other stakeholders,
-) to prove the information for society on topicalities in innovative drug development and results of the InnovaBalt,
WP7. External Assessment of LIOS
Objectives of WP7:
-) to evaluate the implementation of the project, including a new SWOT analysis and updated Strategy relevant to the current situation,
-) to get an independent opinion about LIOS capacity (including management and IPR management) for its further development,
-) to optimize LIOS integration in ERA by increased contribution to regional economic and social development and for better participation in FP projects
WP8. Management
Objectives of WP8:
-) to set up the appropriate monitoring, coordination and communication procedures in order to ensure that project is implemented in a timely and cost effective manner in accordance with applicable EC guidelines and national legislation rules,
-) to ensure that EC financial and administrative procedures are respected and reports and cost statements are provided in time.
The InnovaBalt project implementation was well aligned to all major activities of the LIOS strategic research program:
-) new drug targets, medicinal chemistry,
-) development of synthesis methodology, scale-up and optimisation,
-) in silico modelling, structure biology,
-) biophysical and biochemical screening, bioanalytical assays,
-) in vitro, in vivo activity testing systems, toxicity, pharmacokinetis, ADME.
External experts nominated by the EC evaluated the InnovaBalt project as excellent in terms of results and increase in research quality performed at the LIOS. The new equipment and the secondments supported by the InnovaBalt, where the driving forces for the LIOS researchers to establish and/or reinforce international collaborations with the pharmaceutical industry and top research groups from academia, leading to an increase of the number of publications in high impact factors journals in the areas of chemistry/structural biology/pharmacology. The InnovaBalt also allowed the LIOS to attract young Latvian researchers that were abroad, which brought their acquired know-how to the institute.
Project Results:
Please provide a description of the main S & T results/foregrounds. The length of this part cannot exceed 25 pages.
Implementation of the InnovaBalt (recruited researchers, upgraded scientific equipment, exchange of experience, trainnings of staff) has essentially increased the research capacities and capabilities of LIOS. New collaborative research projects started since 2015 reflect the main S&T results of the InnovaBalt.
Horizon 2020 projects
1. Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets, www.integrate-etn.eu
Acronym: INTEGRATE, Contract number: 642620
Funding scheme: MSCA-ITN-ETN – Training Networks
Implementation period: 01.01.2015. – 31.12.2018
Costs for Latvian partner: 223 577,64 EUR
Project coordinator: University of Parma, Italy
Project partners: University of Helsinki (Finland), University of Eastern Finland (Finland), Latvian Institute of Organic Synthesis (Latvia), The Chancellor, Masters and Scholars of the University of Cambridge (UK), University of Ljubljana (Slovenia), Taros Chemicals GMBH & CO KG (Germany), University of Antwerp (Belgium), Aptuit, Verona SRL (Italy), Fraunhofer Gesellschaft zur Forderung der Angewandten Forshung EV (Germany).
Summary
Antimicrobial resistance is posing a continuously-rising threat to global health. The INTEGRATE project has assembled a team of 10 beneficiaries from eight EU member states, encompassing both academic and non-academic sectors and different disciplines, to form a consortium committed to training Early Stage Researchers (ESRs) in the discovery and preclinical validation of novel Gram-negative antibacterial agents and antibacterial targets. The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure is accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. The intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.
2. Peptidomimetics with photocontrolled biological activity www.pelico.org
Acronym: PELICO, Contract number 690973
Funding scheme: MSCA-RISE – Research and Innovation Staff exchange
Implementation period: 01.01.2016. – 31.12.2019.
Costs for Latvian partner: 103 500 EUR
Project coordinator: Enamine, Limited Liability Company (Ukraine)
Project partners: Karlsruhe Institute of Technology (Germany),
Latvian Institute of Organic Synthesis (Latvia),
The Chancellor, Masters and Scholars of the University of Cambridge (UK).
Summary
The expertise, resources and specific knowledge of all participating parties will be combined to achieve a breakthrough in design, synthesis and application of peptide analogues (peptidomimetics) possessing photo-controlled biological activities, with special emphasis on anti-microbial and anti-cancer activities. The main idea behind the Project consists in chemical incorporation of artificial photo-controllable building blocks into known biologically active peptides by replacing their natural building blocks – the amino acid residues. Such a modification would provide photocontrolled peptidomimetics which can reversibly change their structure between two different photo-forms upon irradiation with light of different wavelength. The participating parties possess general know-how for design of the peptidomimetics which can exist in two photo-forms, biologically active and inactive ones, reversibly interconvertible by light of different wavelength. This opens a possibility to convert inactive peptidomimetics to active compounds by irradiation with physiologically benign light directly in tissues with very high spatiotemporal precision and can be a fundamental basis of new therapeutic strategies. The research staff exchange and other activities planned under the Project will be dedicated to accomplish four complementary work packages:
-) carrying out pharmacokinetic and toxicity studies of the photocontrolled peptidomimetics synthesized by the parties previously;
-) evaluation of novel photocontrolled building block chemotypes for their compatibility with peptides;
-) creation of new photocontrolled peptidomimetics, especially based on the novel building blocks and the know-how developed by the parties (e.g. using “stapled peptides” technology);
-) multidisciplinary training of the researchers whose future work will be aimed at further development of the most advanced photocontrolled peptidomimetics as drugs suitable for photodynamic therapy.
3. Developing new therapies for Batten disease, www.batcure.eu
Acronym: BATcure, Contract number 666918
Funding scheme: Research and innovation action
Implementation period: 01.01.2016. – 31.12.2018.
Costs for Latvian partner: 399 625 EUR
Project coordinator: University College London (UK),
Project partners: AcureOmics AB (Sweden), Latvian Institute of Organic Synthesis (Latvia), Cardiff University, (UK), Fondazione Telethon (Italy), Medical Center Hamburg-Eppendorf (Germany), Pronexus Analytical AB (Sweden), The Manchester Metropolitan University (UK), The Royal Veterinary College (UK), University of Salamanca (Spain), Orphazyme APS (Denmark), King’s College London (UK),
Acondicionamiento Tarrasense Associacion (Spain), Batten Diseases Family Association (UK).
Summary
The goal of BATCure is to advance the development of new therapeutic options for a group of rare lysosomal diseases – neuronal ceroid lipofuscinoses (NCL) or Batten disease. There are > thousand affected across Europe, with a combined incidence of c.1:100 000. The NCLs are devastating and debilitating genetic disorders that mainly affect children, who suffer progressive dementia and motor decline, visual failure and epilepsy, leading to a long period of complete dependence on others, and eventually a premature death. Existing palliative treatment can reduce, but does not eliminate, the burden of seizures and the progressively worsening effects on the whole body due to decreasing CNS influence and control. There are no curative treatments in the clinic for any type of NCL. BATCure will follow a novel integrated strategy to identify specific gene and small molecule treatments for three genetic types of Batten disease that include the most prevalent world-wide, juvenile CLN3 disease, and in southern and mediterranean Europe, CLN6 and CLN7 diseases.
To develop new therapies for these 3 types of Batten disease, BATCure will:
- Create new models, tools and technologies for developing and testing therapies,
- Further delineate disease biology and gene function to identify new therapeutic target pathways utilising yeast and pluripotent stem cell models,
- Identify biochemical therapeutic target pathways, facilitate effective evaluation of preclinical therapies and improve diagnostics,
- Extend a comprehensive natural history beyond the brain to include cardiology, the spinal cord, PNS, psychiatric and metabolic changes,
- Identify new and repurpose existing small molecule therapy,
- Triage new compound treatments in zebrafish, a high-throughput small vertebrate model,
- Deliver and monitor new treatments using mouse models,
- Provide a novel mechanism to involve patients and their families to inform and fully contribute to therapy development and prepare for clinical trials.
4. Baltic Biomaterials Centre of Excellence.
Acronym: BBCE, (under contract negotiations)
Funding scheme: H2020-WIDESPREAD-04-2017-TeamingPhase1
Implementation period: 01.09.2017. – 31.08.2018.
Costs for Latvian partner: 56 000 EUR
Project coordinator: Riga Technical University,
Project partners: AO-Forschungsinstitut Davos (Switzerland), Friedrich-Alexander-
Universität Erlangen Nürnberg (Germany), Latvian Institute of Organic Synthesis,
Riga Stradins University.
Summary
The Rudolfs Cimdins Riga Biomaterials Innovations and Development Centre (RBIDC) is a part of Riga Technical University, Latvia (RTU). The RTU RBIDC research team is composed of chemists, chemical engineers and materials scientists. RTU RBIDC scientists are working on well-defined materials science research areas for bone tissue replacement and regeneration. There has been a long lasting cooperation between RTU RBIDC and the Latvian Institute of Organic Synthesis (LIOS) on investigations of biomaterials developed in RTU RBIDC. LIOS has vast experience in preclinical testing of biological/pharmacological activity in in vitro and in vivo systems. Biomaterials developed at RTU RBIDC, in cooperation with clinicians from the Riga Stradins University, Latvia (RSU), have been tested in clinical practice in more than 400 patient cases. RTU RBIDC research fields and scientific capacity will be the core for establishing a new Baltic Biomaterials Centre of Excellence (BBCE) and by adding the crucial experience of RSU and LIOS research fields, full-cycle development of biomaterials will be covered and infrastructure, to create critical mass and excel at specific field and create spill-over effects between different fields. Within the formation of critical mass in research and development, also the cooperation between industry and research organisations will be encouraged, leading to technology transfer and delivery of new products in the market. Hence BBCE project´s main objective is to establish a joint Baltic Biomaterials Centre of Excellence for advanced biomaterials development based on the long-term strategic cooperation between AO Research Institute Davos, Switzerland and Friedrich-Alexander University of Erlangen-Nuremberg, Germany on the one hand and RTU RBIDC, LIOS and RSU on the other hand.
5. Development of high-field DNP-enhanced MAS NMR techniques for structure
determination of viral capsids.
Acronym: virus-DNP-NMR, Contract number 661175
Funding scheme: MSCA-IF-EF Marie Skłodowska-Curie Individual Fellowships
Implementation period: 01.09.2015. – 31.08.2017.
Project coordinator: Centre de RMN à Très Hauts Champs, Ecole Normale Supérieure
de Lyon, CNRS (France), the InnovaBalt strategic partner
Fellow: Dr.Kristaps Jaudzems, Latvian Institute of Organic Synthesis
Summary
The atomic-level characterization of large viral particles is one of the greatest challenges of modern structural biology, as well as a fundamental step for the design of effective antiviral treatments. In viruses, the viral genome (double- or single-stranded RNA or DNA) is associated to multiple copies of a capsid protein, forming predominantly icosahedral or helical architectures. These complex superstructures are often studied by X-ray crystallography and electron microscopy (EM). However, only information at low resolution is usually available from EM, and extended and flexible architectures do not provide single crystals amenable to diffraction studies. Over the last years, solid-state NMR (ssNMR) has developed into a powerful structural tool for studying structure and dynamics of solid biological samples at atomic resolution and is now uniquely positioned to complement diffraction-based techniques for the characterization of large functional assemblies.
However, proteins of large size or that are available in limited amounts are still inaccessible to site-specific NMR studies. Exploiting a unique equipment available in the host institution, the project aims to remove the current bottlenecks and develop improved dynamic nuclear polarization (DNP)-enhanced ssNMR methodology to push forward the limits of applicability of this technique to macromolecular assemblies, opening new avenues to ssNMR in structural biology. Innovative experimental approaches will be developed to overcome the resolution barriers that currently limit the application of high-field DNP, and new spectroscopic tools will be introduced to allow the structure determination of biomolecules under DNP conditions. The effectiveness and versatility of the newly developed methods will be tested on two viral nucleocapsids of different architectures, the icosahedral capsid of non-tailed bacteriophage AP205 and the filamentous, helical nucleocapsid of Measles virus.
EUROSTARS-2 project
6. Super Biased Ligands for Treatment of Type II Diabetes, https://www.eurostars-eureka.eu/project/id/10635
Acronym: SUBERB, Contract number 10635
Implementation period: 01.09.2016. – 31.08.2019.
Costs for Latvian partner: 209 995 Euro
Project coordinator: Atrogi AB (Sweden)
Project partners: Maastricht University (The Netherlands), Stockholm University
(Sweden), Latvian Institute of Organic Synthesis
Summary
Type-2 diabetes is spreading faster than any other disease in the world. In just twenty-five years, the number of people with diabetes has exploded from 30 million people (1985) to 347 million (2012), with recent figures (2016) up to 415 million, and estimated to reach considerably above 500 million people within the next ten years. The largest increase comes from populations in China, India and the Middle East establishing this disease as a global problem. Consortium of project would like to meet this challenge and exceed or complement the current treatment options in todays multi-billion Euro diabetes market. SUBERB addresses this challenge by delivery of a super biased compound for the treatment of type 2 diabetes. This compound through a novel, insulin independent signaling pathway will stimulate glucose uptake in peripheral tissues In this project it is planned to optimize structure of investigated compounds to obtain a prenomination candidate drug (preCD) that can be advanced towards clinical trials, and ultimately, to the large diabetes market. The goal is to deliver at least one compound that meets the standards of a preCD. The compound(s) will be protected by one or more patent applications covering the compound(s) per se and their use in the treatment of type 2 diabetes.
ERA-NET projects
7. Neuroinflammatory mechanisms of chronic neurodegeneration and cognitive decline
following traumatic brain injury, http://www.neuron-eranet.org/_media/Plesnila.pdf
Acronym: CnsAflame
Call: ERA-NET NEURON JTC2014 “Neuroinflammation”
Implementation period: 01.04.2016. – 31.03.2019.
Costs for Latvian partner: 209 990 EUR
Project coordinator: Ludwig-Maximilians University, Institute for Stroke and Dementia, Munich (Germany)
Project partners: University of Bordeaux (France), Latvian Institute of Organic
Synthesis, Uppsala University Hospital, Uppsala (Sweden), The Hebrew University
(Israel), University Hospital Würzburg (Germany).
Summary
Traumatic brain injury (TBI) is the leading cause of disability and death in Europe among young adults and children and an increasing problem in the elderly. While the acute mortality of TBI was reduced in recent years due to improved emergency and hospital care, it has become evident that surviving patients often develop progressive brain atrophy and dementia (chronic TBI) of unknown origin resulting is significant morbidity. Recent animal and human studies suggest that chronic TBI might be accompanied by neuroinflammation. The hypothesis of the current application is that acute TBI triggers a chronic neuroinflammatory response which causes progressive post-traumatic neurodegeneration, cognitive decline and dementia. The scientific aim of the current project is therefore to characterize and understand long-lasting neuroinflammatory changes occurring after TBI and to use this knowledge for developing novel therapeutic strategies which may protect the brain from chronic post-traumatic atrophy and functional decline.
In order to achieve this overall goal, CnsAflame project brought together six internationally competitive research groups with unique experience in TBI and neuroinflammation research and will use state-of-the-art technology (tissue clearing and 3D imaging by light-sheet microscopy, ultra-high field 17.6 T MRI, 2-photon microscopy, 3T PET/MRI) to investigate post-traumatic neuroinflammation in animal models of TBI and in TBI patients. Thereby a unique translational research platform will be created which has the means and the potential to generate novel therapeutic concepts for patients suffering from chronic TBI.
8. Screening and developing of a novel family of natural and synthetic HIV
Integrase inhibitors which do not interfere with V(D)J recombination
Acronym: INinRAGI
Call: ERA-NET HIVERA JTC2014 “European Research Projects on HIV/AIDS”
Implementation period: 01.09.2015. – 31.08.2018
Costs for Latvian partner: 150 000 EUR
Project coordinator: Clinical Hospital Colentina (Romania)
Project partners: University of Szeged (Hungary), Institute of Biochemistry of The Romanian Academy, (Romania), Latvian Institute of Organic Synthesis, National Center for Epidemiology (Hungary)
Summary
After birth newborn infants from HIV infected mothers have to be subjected to prophylactic treatment to prevent viral infection. HIV Integrase(IN) is the enzyme that mediates the viral genome integration into the host cells chromosomes and its catalytic prevention represents a major way to stop the viral infection. Despite its major clinical advantages the treatment with IN inhibitors(INi) in newborns induces a paradoxical situation. Because HIV-IN resembles in its structure and reaction mechanism to RAG1 protein, which assembles the lymphocytes antigen receptors, INi medication interferes with the ability of treated patients to develop a normal immune response. INinRAGI project is targeted to solve the major drawback of INi treatment that it cannot be addressed to newborns exposed to high risk acquiring HIV-1 infections. The major goal of project is to test new HIV specific Integrase inhibitory compounds which do not interfere with RAG somatic recombination. Project proposes to develop rapid, low cost, efficient FRET screening assays. With them will be HTP screen first a library of natural compounds (NP) of herbal origin. Informed by the best selected NPs we will in silico design and synthesize a derivatized set of HIV-INi compounds which will be again screened in vitro for dual HIV Integrase inhibition and RAG noninterference effects. The uniquely discovered lead compounds will also be tested in immune B cell progression assays and for their antiretroviral potency on HIV infected T cells.
9. Study of the new post-replicational modification of DNA by Poly(ADP-ribose)
polymerases and its implication for anticancer therapy
Acronyme: DNA PARYLATION
Call: ERA-NET RUS-PLUS JTC2015 “Joint call on Science and Technology” Implementation period: 01.01.2016. – 31.07.2018.
Costs for Latvian partner: 60 000 EUR
Project coordinator: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk (Russia)
Project partners: Centre National de la Recherche Scientifique, UMR 8200 Stabilité génétique et oncogenèse, Villejuif (France), Latvian Institute of Organic Synthesis.
Summary
The aim of the present study is to obtain new insights into the molecular mechanisms of PARPs mediated regulation of DNA repair, DNA transcription, chromatin dynamics and cell death. Our preliminary studies suggest that the Poly(ADP-ribose) (PAR) polymerases, PARP1 and PARP2 can covalently modify not only acceptor proteins but also DNA termini at strand breaks by transferring ADP-ribose units to 3'-hydroxyl and/or 3'-phosphate at the end of a gap and to 3'-hydroxyl of a nucleotide at the end of a double-strand break.
Project proposes to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.
The project is structured of four complementary tasks:
- Examination whether the PARylated termini of DNA strand breaks block DNA replication fork progression and inhibit the toxic non-homologous end-joining.
- Identification of PAR-DNA Adducts in living cells using biochemical and biophysical approaches.
- Biochemical characterization of substrate specificities of the members of PARP protein family.
- Development of new PARP and PARG inhibitors (directed by Latvian partner).
The major objectives of this task are to clarify the role of PARP and PARG proteins in DNA repair and to find new inhibition strategies. Recent results of Latvian team indicate that some derivatives of 1,4-dihydropyridines (1,4-DHPs), possessing anti-mutagenic activity can interact directly with DNA and, unexpectedly, with PARP1. This opens a possibility for search of novel inhibitors of PARP1 among 1,4-DHPs. Here, we propose to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.
10. Innovative Nanopharmaceuticals: Targeting Breast Cancer Stem Cells by a Novel
Combination of Epigenetic and Anticancer Drugs with Gene Therapy.
Acronyme: INNOCENT
Call: ERA-NET EuroNanoMed-II 2016
Implementation period: 01.04.2017. – 31.03.2020.
Costs for Latvian partner: 209 770 EUR
Project coordinator: Biomedical Research Centre, Slovak Academy of Sciences (Slovakia)
Project partners: Latvian Institute of Organic Synthesis, Hospital Universitari Vall d’Hebron (Spain), University of Bergen (Norway), Norwegian Institute for Air Research (Norway), eNIOS , private company (Greece).
Summary
The last decade has seen a flourishing in the study of the properties of nanoparticles for medical applications. The next generation of nanopharmaceuticals combine a series of advances which enable the creation of multimodal/multifunctional nanodrugs that may contain anti-tumour agents, targeting ligands designed to home in on malignancies together with imaging agents to light up even the earliest stage of cancers. The nanotechnology in combination with conventional chemotherapy, gene therapy and epigenetics opens the door to novel therapeutical approaches. The aim of the INNOCENT project is to develop innovative multifunctional nanopharmaceuticals to overcome the low efficacy and frequent relapses in breast cancer (BC) treatment, with emphasis on cancer stem cells (CSCs). The proposed multimodal COMBOBOMB, brilliantly integrates the diagnostic and therapeutic functions within a single nanostructure. The COMBOBOMB harbours four major components: 1) a selective targeting moiety (chitosan-targeted CD44); 2) a diagnostic imaging aid for localization of the malignant tumour and its micro- or macrometastases (inorganic nanocrystals); 3) a cytotoxic drug (doxorubicin), and 4) a chemosensitising agent (decitabine, DAC along with DAC-activating enzyme) utilising gene therapy and epigenetic approaches. The inorganic nanocrystals entrapped in the nanocarrier will allow real time non-invasive imaging of the COMBOBOMB biodistribution and accumulation at the tumour site, and will allow the monitoring of patients` response to treatment. The rationally designed multifunctional nanodrug will offer new possibilities of penetration into CSC niches and open new horizons for treatment of tumour cells in bulk and CSCs. The COMBOBOMB has the potential to be used also as neoadjuvant therapy, to decrease the probability of tumour cell dissemination (mainly via the CSC subpopulation). Moreover, this multifunctional nanotherapeutical could increase the efficacy of radiotherapy by ehancing radiosensitization of tumour tissue. The COMBOBOMB represents a new generation of nanomedicine with enhanced potential for both therapeutic treatment and decreased recurrence of BC, with potentially high impact on survival and quality of life of BC patients. This multidisciplinary, highly collaborative bench-to-bedside approach will provide both economic impact and added value for public health.
11. Time dependent Remote Alterations after Injury to the Nervous System
Acronyme: TRAINS
Call: ERA-NET NEURON JTC2016
Implementation period: 01.06.2017. – 31.05.2020.
Costs for Latvian partner: 209 000 EUR
Project coordinator: CNRS - Université de Bordeaux (France),
Project partners: University of Munich (Germany), Weizmann Institute of Science (Israel), UMR1141 Inserm - Paris Diderot University (France), Medical University of Lodz (Poland), Latvian Institute of Organic Synthesis.
Summary
Injury to the brain or the spinal cord results in long term functional deficits in affected patients which mainly affect sensation and motor function. Traditionally it was believed that these impairments are solely caused by the initial local brain damage. However, an increasing body of evidence now indicates that in addition to the acute local changes also distant areas of the brain connected to the primarily injured area are also critically involved in this process.
The main hypothesis underlying this project is that sensori-motor dysfunction (smD) following a focal injury to the central nervous system is associated with remote alterations occurring distant from the primary lesion site (remote brain injury, remBI). Since the mechanisms of remBI are largely unknown, the aim of the current application is to understand how, where, and when remBI occurs after traumatic brain (TBI) and spinal cord injury (SCI) and to use this knowledge for the development of novel therapeutic strategies for patients suffering from long-term dysfunctions after CNS injury. For this purpose we put together a consortium of excellence with internationally recognized experts in the field of CNS injury with surpassing expertise in the investigation of the brain and the spinal cord. This consortium will study remBI in neonate, juvenile, adult and aged rodent models of TBI and SCI by using state-of-the-art and newly developed in vivo (small animal, MRI, 2-photon microscopy, bio-orthogonal chemical reporter) and ex vivo (viral tracing, tissue clearing) technologies. The first work package (WP1) will investigate the temporal and spatial profile of neuronal reorganizations and inflammatory processes for up to 6 months after injury. Brain and spinal cord tissue will be studied and correlated with changes in smD. The WP2 will decipher the key cellular and molecular mechanisms with a focus on the neuronal connectivity (dendrites, axons, spines and synapses), immune-glial cell interactions (monocytes, microglia, astrocytes), and vascular changes (endothelial cells, pericytes, astrocytes). Finally, WP3 will identify potential treatments for smD: 1) stabilization of glial and neuronal microtubules, 2) adaptive transfer of monocytes, and 3) inhibition of JNK pathway. These studies will be performed using a pre-clinical multi-center trial design. Newly developed in vivo and ex vivo CNS imaging technologies together with state-of-the art treatment will be used. This project will establish a long-term collaborative network of excellence and provide a future basis for the design of novel therapeutic strategies, which will outlive the current funding period.
12. Engineering and functionalization of delivery system with Pelargonium sidoides
biologically active substance on inflamed periodontal surface area.
Acronyme: PELARGODONT
Call: M-ERA.NET JTC2016
Implementation period: 01.06.2017. – 31.05.2020.
Costs for Latvian partner: 45 650 EUR
Project coordinator: Lithuanian University of Health Sciences (Lithuania)
Project partners: Centre of Polymer and Carbon Materials Polish Academy of Sciences (Poland), Latvian Institute of Organic Synthesis, Jagiellonian University in Krakow (Poland), Riga Stradins University (Latvia), Università Piemonte Orientale (Italy), UAB Ferentis (Lithuania).
There are many patients in dental practice who have some form of periodontal disease. Periodontal diseases range from simple gum inflammation to serious disease that results in major damage to the soft tissue and bone that support the teeth. In the worst cases, teeth are lost. Common strategy for treatment of periodontitis treatment include use of antibiotics and synthetic antiseptics that is accompanied by systemic side effects and increased bacterial resistance. Such strategy is not suitable for prolonged or repeatable treatment and fails to stop disease remission and further progression. This creates a demand for local delivery devices with multiple antibacterials of mild action. The aim of this project is to engineer and functionalize a biodegradable mucoadhesive drug delivery system of local action with natural active substance for periodontitis treatment. To avoid negative impact of antibiotics and synthetic antiseptics, a set of natural biologically active compounds from Pelargonium sidoides is chosen as an alternative prevention and treatment option. The system will be designed to release optimized levels of multiple antibacterials from Pelargonium sidoides root extract in the disease - affected area for a sustained period of time aiming for both ease of use and high patient acceptance. The system will be designed from biodegradable polymer- peptide carriers.
The project will start from a preformulated concept (TRL 2) for the delivery system of biodegradable carrier and antimicrobial active substance. During the 24 month research the concept will be developed to the form of prototype (TRL 5) and demonstrated as an active medical device in a clinical trial. Technology will be validated and fabrication process optimized together with UAB Ferentis, a research intensive biotechnology company involved in the development of biomaterials for in vitro cell cultures, tissue engineering and regenerative medicine applications. The implementation of the project will consist of three main workblocks: 1) investigation of the protective and antibacterial effects of the active substances in vitro studies and investigation of delivery material, 2)construction and development of a local delivery device prototype, and 3) local delivery device prototype testing in a clinical trial.
Scientific research performed will prepare the ground for new methodology to design interfaces between natural biologically active substances in a biodegradable carrier and periodontal inflamed surface area. The project will deliver an innovative product that will help avoid or delay surgical treatment, and prevent side effects including hypersensitivity, gastrointestinal intolerance and development of bacterial resistance.
Projects of mutual fund Taiwan – Latvia – Lithuania
12. Design of anticancer pharmaceutical compounds using structure and energetics of
lead – target interactions
Implementation period: 01.04.2016. – 31.03.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: National Central University (Taiwan), Latvian Institute of Organic
Synthesis, Vilnius University (Lithuania)
Summary
Rational drug design begins with the phase of discovering lead compounds that strongly interact with target proteins and could be modified, improved and developed into pharmaceuticals. Epigenetic targets are currently considered as one of the most exciting biological target areas to be tackled with drugs against numerous diseases.
Epigenetic mechanisms are inheritable factors that regulate genetic expression and chromatin architecture without changing the DNA sequence. These factors are DNA methylation, histones modifications (methylation, acetylation and phosphorylation), activity of various non histones proteins that bind to the DNA and small regulatory RNAs. Epigenetic enzymes regulate histones and DNA changes by these simple chemical modifications and determine whether genes are turned on or off, and deregulation of the processes plays a central role in several diseases.
Numerous studies have shown the efficacy of epigenetic drugs in hematologic malignancies and several more are showing that epigenetic drugs when used in combination with anti-cancer drugs are driving solid tumor treatment. According to the Structural Genomics Consortium, there are 377 known epigenetic targets. But epigenetics has so far yielded only four approved drugs.
The three research teams of this project have combined their efforts to improve the knowledge of protein – drug recognition and to make compounds that would be proposed to develop as drugs primarily against cancer. All three teams have significant experience and continue to use the target-based drug discovery approach. Protein targets will be a part of the epigenetic proteins, mostly metalloenzymes containing zinc in their active site. Metalloenzymes are widely distributed in human body and their loss of activity or misregulation causes numerous diseases.
Choosing similar target proteins helps by grouping the compounds to a limited set of pharmacophore groups that would bind to a particular set of targets. For example, aromatic primary sulfonamides are widely known to tightly and specifically bind and inhibit carbonic anhydrases (CAs). Similarly, hydroxamic acid-containing compounds recognize and bind one group of zinc-containing histone deacetylases (HDACs), a class of epigenetically modifying enzymes.
The consortium proposes to design, synthesize new eventually active compounds and to develop methodology for their activity screening by calorimetry methods. The mechanisms of action would be tested by the X-ray structure studies to develop further more active compounds. All the planned activities logistically follow each other and the new results may optimize the process of development of leading structures.
13. Synthesis and studies of high-triplet-energy materials for blue OLEDs
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: Graduate Institute of Photonics and Optoelectronics (Taiwan),
Latvian Institute of Organic Synthesis, Kaunas University of Technology (Lithuania)
Summary
During the last decades all colour light-emiting diodes (OLEDs) have evolved into commercial applications such as flat-panel low-weight displays or sources of solid state lighting. Today, the efficiency of OLEDs is at product-relevant levels for all colours excepting blue. Therefore, high-efficient blue OLEDs with industry-standard device lifetimes have to be realized to fully open the potential of OLEDs. Recently blue thermally activated delayed fluorescence (TADF) and phosphorescence emitters (having values of triplet levels higher than 2,7 eV) were developed application of which can allow to achieve the internal quantum efficiency of blue OLEDS close to 100 %.
Synthesis and studies of high-triplet energy charge-transporting materials are the main objectives of this joint project. The tasks of the project include development efficiency organic semiconductor materials with high triplet-energy values for new-generation blue OLEDs including the theoretical modelling and designing of charge-transporting materials, their synthesis and characterization of charge transportproperties in solid state, detailed investigation of transport properties in solid state, detailed investigation of transport mechanisms and correlation with molecular structures and morphology etc., fabrication and characterization of light-emitting devices using the most promising materials. OLEDs with the maximum external quantum efficiency higher than 15% will be fabricated and characterized. The turn on voltage of the OLEDs will be lower than 3,5 V. The maximum brightness higher than 5000 cd/m2 will be reached that will unclose the practical applications of blue OLEDs.
14. Understanding prion peptide fibril-induced aggregation of prion protein.
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: Institute of Biological Chemistry, Academia Sinica (Taiwan),
Latvian Institute of Organic Synthesis, Vilnius University (Lithuania).
Summary
Prion-like spreading may be employed in a number of fatal neurodegenerative disorders, including such as Alzheimer’s and Parkinson’s diseases. Understanding all possible mechanisms of such spreading would be a big step towards curing these diseases.
Recent work showed that prion protein aggregation can be induced by short peptides. It seems that either structure of peptide-induced prion protein aggregation (piPrP) or the mechanism of its formation is different from the current knowledge in the field. Project is targeted to the comprehensive study of piPrP structure, starting from low resolution methods as Fourier transform infrared (FTIR) spectrometry and proteinase K resistance studies, but focusing on medium and high resolution methods in hydrogen exchange mass spectrometry, and solid state nuclear magnetic resonance spectroscopy. High resolution structure will lead to the ultimate goal of project – getting deeper into mechanisms of prion-like self-replication of amyloid fibrils.
15. Nanoarchitectonics of Metal-Organic Frameworks (MOFs): Design, Dielectric
Property, and Organic Catalysis
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 68 169 EUR
Project partners: National Taiwan University (Taiwan), Latvian Institute of Organic
Synthesis, Vilnius University (Lithuania)
Summary
Project is focused on the design and synthesis of novel metal organic frameworks (MOFs), and the application of this class of materials on catalysis and membrane separations. MOFs possess highly ordered nanopores, good tenability for interior surface properties, and high porosity. These materials have drawn a great research attention in the past decade due to their potentials on catalysis, adsorption and electrophotonics. This work is aimed at two specific application fields, membrane separation and catalytic asymmetric reactions. Consortium will employ the concept of molecular self-assembly on designing and tuning the multiscale microstructure for prevaporation and asymmetric reactions. The self-assembly mechanisms of MOF materials will be studied and then new MOFs exclusively for the specific catalytic reactions and the separation systems will be synthesized. Subsequently, the cutting-edge characterisation techniques and homemade instruments will be applied to perform a comprehensive structural and functional characterisation. This project is expected to create high impact on both nanomaterials and catalytic reactions.
EEA and NORWAY Grants
16. Benefits and detrimental effects of sequence variants of Amyloid-β: towards the use
of small peptides for aggregate dissolution therapy in dementia.
Implementation period: 01.05.2015. – 30.04.2017.
Costs for Latvian partner: 166 711 EUR
Project coordinator: Latvian Institute of Organic Synthesis
Project partners: University of Latvia, University of Oslo (Norway)
Summary
The overall goal of this project is to develop the new strategy for the treatment of the Alzheimer disease (AD) and to enhance research-based knowledge in Latvia through a long term collaboration between project partners. The research group of Latvian Institute of Organic Synthesis will provide expertise in structural analyses to start an iterative set of experiments. The University of Oslo will provide knowledge and expertise in the field of disease models and analyses. The researchers of University of Latvia will have access to world-wide unique mouse models, and are skilled in the performance of behavioural and cognitive tests. The outcome from this Latvian-Norwegian research cooperation project will be the identification of neuroprotective properties of short N-terminal peptides of Aβ for their propensity to remove toxic Aβ peptide deposits and improve cognitive functions which may introduce new options in AD therapy.
17. Image-guided cancer gene therapy in combination with advanced chemotherapeutics
Implementation period: 01.05.2015. – 30.04.2017.
Costs for Latvian partner: 140 000 EUR
Project coordinator: Latvian Biomedical Research and Study centre
Project partners: Latvian Institute of Organic Synthesis, University of Oslo Hospital
(Norway)
Project overall objective is to develop an efficient strategy for cancer treatment based on application of image-guided targeted chemotherapeutics in combination with viral gene therapy vectors. Project presents a new collaborative research initiative within the field of cancer therapy. Project consortium proposes to apply novel alphaviral vectors encoding cytokines, which able to stimulate tumor-associated macrophage (TAM) infiltration into the tumor and induction of pro-inflammatory microenvironment to block tumor recovery after chemotherapy. Several mouse models of breast cancer, melanoma and xenograft model of human lung carcinoma will be treated with chemical compounds with significant anti-proliferative properties followed by the application of alphaviral vectors. The outcomes of treatment will be monitored using advanced imaging technologies including bioluminescent and fluorescent imaging. The molecular mechanism underlying the alphaviral tumor tropism will be investigated in details using a comparative proteome analysis of cancer cells susceptible and unsuceptible to alphaviral invection. Therefore, the aim of this study is to develop an efficient strategy for cancer treatment based on an application of image-guided targeted chemotherapeutics in combination with gene therapy vectors. Special attention will be paid to training of young researchers in cutting-edge imaging techniques, advanced immunological methods and mass spectrometry approaches. The research credibility is justified by the broad and complementary expertise of participating groups from three institutions Latvian Institute of Organic Synthesis, Latvian Biomedical Research and Study Centre and Oslo University Hospital.
Ukraine – Latvia collaboration project
18. Elaboration of fluorine containing amphiphilic heterocycles as delivery systems and
evaluation of their self-assembling properties with perspective as new materials for
use in biomedicine.
Implementation period: 01.01.2017. – 31.12.2019.
Costs for Latvian partner: 40 000 EUR
Project partners: Latvian Institute of Organic Synthesis, Institute of Organic
Chemistry, National Academy of Science of Ukraine.
Summary
The aim of this project is the elaboration of new kinds of nanoparticles formed by cationic lipids with fluorine containing substituents as the potential transmembrane delivery agents in cooperation experience between research groups from Latvia and Ukraine. This aim will be achieved by the implementation of the following objectives:
1) Synthesis of the original fluorous containing building blocks:
alcohols, esters of acetoacetic acid and 3-aminobut-2-enoic acid esters, benzaldehydes;
2) Design and synthesis of the original delivery systems with improved properties:
construction at 3,5-positions of 1,4-DHP cycle AlkH or AlkF containing esters,
introduction of various fluorine containing phenyl substituents at the position 4 of
1,4-DHP cycle,
exchange of H to F atom at the position 4 of DHP cycle,
variations of F-containing pyridines at the positions 2,6 of DHP cycle.
3) Characterisation of self-assembling properties of new fluorine containing delivery
systems with improving properties.
4) Dissemination of the results in SCI journals and international conferences at both countries.
Implementation of this project will give a contribution for the achieving the aims of the strategy of nanotechnology which is one of the six Key Enabling Technologies and has a significant impact on many different medicinal developments in the three main areas: Therapeutics, Diagnostics/Imaging and Regenerative Medicine.
Osmosis programme (collaboration with France)
19. Multivalent Inhibitors of Bacterial Carbonic Anhydrases: Molecular Innovation in the Field of Anti-infective Agents
Implementation period: 01.03.2016. – 28.02.2018.
Costs for Latvian partner: 4000 EUR
Project partners: Latvian Institute of Organic Synthesis, Université de Montpellier
(France).
Summary
The main objective of project is to develop long-lasting collaboration between research groups of the LIOS and Université de Montpellier (France).
The scientific aim of project is to develop homotopic and heterotopic multivalent systems by molecular engineering, starting from cyclopeptidic scaffold, in order to study the importance of the multivalent effect on the activity and selectivity of inhibition of bacterial carbonic anhydrases.The project is based on the complementary skills of both groups:
The French team has proven expertise in the development of modulators of activity of human and bacterial carbonic anhydrases. In the development of innovative synthetic methodologies for the effective preparation of bioconjugates multifunctionalized by a "click" self-assembly approach using biocompatible and chemoselective ligations. We have already prepared multivalent nanoconstructions based on functionalized cyclic peptides that have proven to be very effective for the recognition of lectins or integrins. A multifunctional compound combining integrin recognition properties and fluorescence imaging was later developed and successfully applied to the in vivo tumor imaging for assisting surgery. The LIOS team has proven expertise in the design and synthesis of highly potent and isoform selective inhibitors of human carbonic anhydrases. Latvian team has developed reliable synthetic methodology for the synthesis of coumarin bioisosteres – 1,2-benzoxathiine 2,2-dioxide or so called sulfocoumarins. The LIOS researchers also have developed several methodologies for the derivatization of sulfocoumarins, including C-H activation and click chemistry. It has been demonstrated that sulfocoumarins are highly selective inhibitors of several human CAs with the inhibition activity in low nanomolar range.
During the project will be implemented mutual visits for the development of further joint research projects.
Potential Impact:
The implementation of the Action Plan of InnovaBalt was carried out by the coherent set of measures:
-) exchange of know-how and experience with EU partnering organizations;
-) recruitment of experienced researchers and technical staff;
-) upgrading of research infrastructure;
-) elaboration of a strategic IP development plan for IP management
and innovation capability building;
-) dissemination of knowledge on health and increasing the visibility of InnovaBalt activities at regional, national and EU levels.
Expected impacts achieved during the implementation of the InnovaBalt project are listed below.
1. Better integration of the LIOS in the European Research Area (long lasting partnerships) was reached via
- ) collaborations and exchange of experience with 50 European research institutions in research, IPR, technology transfer and project management issues (outgoing and incoming visits);
-) organization of 12 transnational events, including the workshops on preparation of proposals for Horizon2020 proposal preparation
-) increased visibility of LIOS by communication and dissemination activities.
2. Upgraded RTD capacity and capability (human potential, training of research staff, scientific equipment) was gained by
- ) exchange of know-how and experience via international two-way secondments of experienced scientists and young scientists between the LIOS and leading scientific institutions in the ERA, provided access to complementary equipment resulting in improvement and development of new skills of the LIOS staff,
-) recruitment of experienced researchers (with expertise in drug discovery and preclinical development programmes; bioinformatics and molecular modelling; modern synthetic chemistry with a special emphasis to the development of methods for pharmaceutical industry),
-) reintegration of experienced researchers, former co-workers of LIOS, from abroad;
-) renewal of equipment which is essential for the advanced innovative drug development,
-) systematic training of early-stage and experienced researchers on research, IPR, technology transfer and project management issues .
3. Improved research capacity for effective contribution to regional economic and social development was achieved by
-) increased availability of new LIOS infrastructure facilities to researchers from other regional research centres,
-) organization of regional seminars, workshops, conferences on research, IPR, technology transfer and project management issues,
4. Improvement of participation of LIOS in Horizon 2020 and other important European programmes was reached via
-) improved skills for competitive proposal preparation and successful management by organization of training courses,
-) increased visibility of the LIOS by participation in conferences, information days and brokerage events,
-) organization of targeted proposal preparation workshop intended to help with further identification of relevant calls and partners.
5. Improvement of innovation potential in Baltic region was achieved by
- ) recruitment of experienced specialist in IP issues;
- ) staff exchange with for improving of experience of management in IP and technology transfer
- ) elaboration of Strategic Intellectual Property development plan for the LIOS;
-) innovation capacity building through the set of trainings for researchers and SMEs in Baltic region;
-) organization of transnational seminar ”Knowledge to innovation” ;
-) actualization of IPR and technology transfer issues in agendas of transnational conferences;
-) Increased awareness of industry partners about the topicalities in the innovative drug research.
All planned measures of the InnovaBalt project were carried out, and expected results were achieved. The fulfilment of the Action Plan has ensured the further sustainability of the LIOS activities. Collaboration with partnering institutions and competence of recruited researchers has increased the total number of publications. There was an increase in the number of publications in journals with impact factor higher than 4 during the last 4 years (starting from 1 paper in 2012 to 16 papers in 2015). The increase of publications in journals with impact factor higher than 4 is evidenced when looking at the average impact factor of LIOS’s scientists publications per year (a 1.7-fold increase from average impact factor = 1.58 in 2012 to IF=2.69 in 2016). Some researchers already published their scientific work in journals with impact factor higher than 10.
LIOS Researchers have participated in the preparation and submission of 22 proposals for Horizon 2020 calls (01.01.2014.-31.12.2016.). From the submitted proposals 4 are successful (success rate 18 %), 16 are above thresholds (without funding) and just 2 proposals were rated below threshold. Ongoing Horizon 2020 projects in LIOS:
-) BATcure - Developing new therapies for Batten disease (contract Nr.666918 funding for LIOS - 399 625 EUR),
-) PELICO - Peptidomimetics with Photocontrolled Biological Activity (Marie Sklodowska-Curie Research and Innovation Staff Exchange Project, contract number: 690973, funding for LIOS - 103 500 EUR).
-) INTEGRATE Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets (Marie Sklodowska-Curie Innovative Training Network Project, contact number: 642620 , funding for LIOS - 223 577,64 EUR)
-) The implementation of theH2020-WIDESPREAD-04-2017-TeamingPhase1 project BBCE (Proposal: 763721; Baltic Biomaterials Centre of Excellence, funding for LIOS – 56 000 EUR) will start in September 2017.
The LIOS was already accepted to enter into 19 different collaborative research project consortia, generating more than 2 million EUR new funding for LIOS. Short annotations of these projects are presented in the final report S&T foreground. These results have become possible through the InnovaBalt activities that focused on international scientific exchange, and increased the visibility and contacts of the LIOS. These data show that within the ranks of European scientific institutions in the field of drug discovery, biochemistry and medicinal chemistry the LIOS is a well accepted partner for scientific work in international consortia. The LIOS current position in the scientific ecosystem is based strongly on the institute’s very well maintained contacts to other researchers and InnovaBalt has been very helpful in enlarging LIOS’s contacts and reach. The research topics that have been pursued under scientific grants focus on several meta-topics: new antibacterial strategies, strategies against cancer, degenerative diseases of the nervous system and other neurologic defects. These meta-topics link with the most interesting and actually most urgent medical problems of our age. LIOS ability to join and perform within these consortia is based on widespread contacts and networking among the European chemical and pharmacological research community, good research infrastructure, staff of researchers and management.
The LIOS is best characterized by a deeply rooted dualism of its activities: the LIOS successfully combines contract research with basic research and through it gains synergy and added value. Both scientific research and contract research are integral parts of the institute, and they will need to remain there in the future. The LIOS has always been focused on manifesting its research results in patents and other forms of intellectual property. The InnovaBalt gave this approach an additional boost through improving the management of intellectual property and through enhancing awareness for the topic among the scientific employees. By making the whole topic of intellectual property transparent for the scientists, a climate of innovation was created at the institute. The InnovaBalt project contributed to the regional economical development through strengthening tight collaboration with industry and innovative drug discovery projects in the LIOS. The InnovaBalt project activities are expected to have long-term social and economic impacts in relation to transformation of the national economy and growth priorities defined in the Latvian Smart Specialization Strategy, especially in RIS3 area of specialization: 2. Biomedicine, medical technologies, biopharmacy and biotechnologies.
Contract research is a large and stable portion in the LIOS’s funding. The average annual share of 42% in the research budget (years 2013 to 2016) is high among European academic institutions. LIOS is best characterized by a deeply rooted dualism of its activities: LOIS successfully combines contract research with basic research and through it gains synergy and added value. Both scientific research and contract research are integral parts of the institute, and they will need to remain there in the future.
Visibility of the LIOS and dissemination activities.
Increased visibility of LIOS has been reached through the regular participation and exploitation of research results in the international conferences and by the organization of international events in Latvia. Manager of InnovaBalt, Professor Maija Dambrova, presented experience and results of InnovaBalt in 3 European events:
-) the workshop during WIRE 2015 „Week of Innovations regions in Europe”, Riga, 3.06. 2015 (Latvia’s Presidency event),
-) the workshop „Contribution of "Research Potential" (REGPOT) and "Regions of Knowledge" (ROK), the way forward thanks to synergies between EU policies/funds”, Brussels , 07.12.2015.
-) Conference “Bridging the Divide in European Health Research and Innovation”, Brussels, 20.10.2016.
In total 68 activities (info in websites, press releases, TV clips, interviews, articles in press, posters, Cafe scientifique, flyers, virtual tour, video) were carried out.
A widely attended press conference took place in the LIOS on February 28, 2017, the last day of the InnovaBalt project implementation. The Coordinator of project Professor Ivars Kalvins, Manager of project, Professor Maija Dambrova and Director of LIOS Osvalds Pugovics presented results achieved during the InnovaBalt project, recommendations of the external evaluation expert panel and plans for the future development and research strategy of LIOS. The representatives from the strategic partnering institutions: the University of Latvia, Riga Technical University, Riga Stradins University, the Association of Latvian Chemical and Pharmaceutical Industry, briefly informed about the examples of successful cooperation with LIOS in the past and intentions for future. The press conference materials were comprehensively reflected in the mass media: 10 TV plots, 18 radio plots, 4 articles in national newspapers and 42 briefings in internet portals (in total 74 communications).
List of Websites:
www.innovabalt.eu
Virtual tour about OSI www.osi.lv/en
Video: https://www.youtube.com/watch?v=FQEzm4XtE8I&feature=youtu.be
