Small RNA-based viruses express only a limited number of proteins and several of these have been shown to form and function as oligomeric species at different points in the virus lifecycle.  The hepatitis C virus (HCV) NS5A protein is critical to both virus replication and assembly and functions as a dimer that forms higher order oligomers.  In this presentation, we will discuss the discovery of lead inhibitors of HCV NS5A and how the observation of the inherent chemical reactivity of some of these molecules in vitro led to the discovery of dimeric compounds that were optimized to the first in class HCV NS5A replication complex inhibitor daclatasvir.  In addition, we will discuss the phenomenon of resensitization of virus that has developed resistance to NS5A inhibitors to inhibition by dimeric compounds that are structurally related to daclatasvir but which are inherently inactive.<br/>

Antiviral drug discovery: Symmetry in the design of HCV NS5A replication complex inhibitors

2019 Fall National Meeting

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