Development and validation of antivirals against hemorrhagic fever viruses of pandemic concern

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SUMMARY Lassa virus (LASV), severe fever with thrombocytopenia syndrome virus (SFTSV), and Ebola virus (EBOV) are hemorrhagic fever causing viruses (HFV) of pandemic concern that pose a threat to public health, a situation exacerbated by an overall lack of effective antiviral therapeutics to combat these infections. Despite their different genome organization and biology, mammarenaviruses (LASV), banyangviruses (SFTSV) and filoviruses (EBOV) share a similar RNA biosynthetic strategy where the viral nucleoprotein encapsidates the viral genome RNA to form a nucleocapsid (NC) that serves as template for RNA synthesis, both replication and transcription, mediated by the associated viral RNA dependent RNA polymerase (RdRp, L protein) in the context of a viral ribonucleoprotein complex (vRNP). The central goal of this Project 6 of CAMPP is to discover and develop antivirals targeting viral components of LASV, SFTSV and EBOV vRNPs. For this, we have on place cell-based and biochemical assays amenable to HTS to identify inhibitors of viral RdRp activity and NC formation for LASV, SFTSV and EBOV, as well as the L protein endonuclease and cap-binding activities required for LASV and SFTSV cap-snatching mediated transcription. Initial hits, identified by HTS using target- specific cell based or biochemical assays, will be validated and, following target confirmation, subjected to a common pipeline involving formal hit assessment (FHA), early and late hit-to-lead (H2L) steps, and lead optimization (leadOP), which will facilitate IND-enabling steps outside the scope of this project. This research project builds on the strong synergy with the CAMPP Cores. The Medicinal Chemistry and Structural and Modeling Cores will use structure-based drug design to synthesize compound derivatives with improved biological and pharmacokinetic properties, whereas the Animal Models of Infection Core will enable in vivo efficacy studies of selected leads.