Discovery of druggable antiviral targets across viral families through chemical probing

Antiviral drugs are used to successfully treat infections such as with HIV and HCV. Yet, for most (life)-threatening and neglected infections, there are no such drugs. This leaves also critical gaps in epi- and pandemic preparedness. Antiviral drug discovery efforts typically focus on a few known targets (e.g., proteases/polymerases) or on "tip-of-the-iceberg-molecules" from phenotypic screens. Yet, the biology of viral replication consisting of complex processes (e.g., entry, uncoating, genome replication, assembly, egress, host cell interactions) should harbor a wealth of undiscovered targets. Thus, a large space of potential druggable biology is entirely ignored. My ambition is to fundamentally revolutionize antiviral target-discovery. Using high-throughput, multiplex, high-content multiparametric phenotypic antiviral screening (>350k molecules) against representative, neglected RNA virus families (rhabdo-, alpha-, and bunyaviruses), we will generate rich multiparametric compound fingerprints. Advanced Artificial Intelligence models will be used to exploit the full complexity of the data to guide the selection of molecules that inhibit or modulate viral replication and that are to be used as unique chemical probes. These will then be systematically characterized through complementary methodologies, including genetic mapping, structural modelling and biochemical validation to obtain detailed understanding of their molecular mechanism of action. The outcome will be a first-of-its-kind "Atlas of Druggable Antiviral Targets", a multidimensional annotation of druggable viral and host targets. Our efforts will expand the antiviral target space, provide new, much needed starting points for (later) target-based drug discovery and hit-to-lead optimization, deepen our understanding of viral replication biology, establish methodologies broadly applicable to other pathogens and ultimately strengthen preparedness against existing and future viral threats.