ProDAP employed proteomic and transcriptomic approaches to identify virus interacting proteins, proteins that change their interaction profile upon virus infection and gene and proteome signatures that are regulated by these interactions. We first established essential tools to study virus-host interactions and protocols that allowed us to monitor the synthesis and degradation rates of proteins (i.e. protein turnover). We found that protein interactions and turnover are indications for involvement of the identified proteins in antiviral processes. Besides systematic analysis of the host protein interactions and protein turnover are critical denominators of virus-driven cellular processes that are associated with disease progression. Functional screens enabled us to identify proteins that have previously not been nkown to play a central importance for virus growth and/or for regulating immune responses. We further integrated knowledge from drug-protein interactions, which enabled us to idnetify molecules that influenced virus grwoth in cell culture and in pre-clinical models and which we promote further for potential therapeutic applications.
More specifically, we used the established tools to monitor the interactions and effects of viruses (e.g. SARS-CoV-2, SARS-CoV: Stulakov et al., Nature, 2021; Bergant et al., EMBO Journal, 2022; Monkeypox virus: Huang et al., Nature Communications, 2024; Influenza A virus: Huang et al., Cell Systems, 2024) and could thereby identify functionally relevant interactions and cellular processes that contribute to virus growth and antiviral processes of the individual viruses. All underlying datasets are publshed in the given manuscripts, deployed in in publically accessible repositories and accessible through websites which enable easy access for fellow scientists. Moreover, we deployed bioinformatics pipelines in public repositories, as mentioned in the manuscripts.
Given the urgency to better understand SARS-CoV-2, we focussed on this virus and could file two patents on bioactive drugs that are regulating the virus and showed favorable activities in vivo. These include one SAM-cycle inhibtior, DZNep, which inhibited SARS-CoV-2 in vitro and in vivo (Bergant et al., EMBO Journal, 2022). Interestingly, this compound not only reduced virus growth but also tamed pathology-driving inflammatory processes and improved antiviral immunity. Another compound we patented is an IKK inhibitor, which similarly reduced virus growth and is known to inhibit inflammation in vitro and in vivo.
The success of ProDAP showcases that basic knowledge on the principles of virus-host interactions can be explored to identify novel therapies that may be used for intelligent design of treatment options against virus diseases. Therefore the work within this ERC program lays the foundation for future clinical developments.
