AZD-7295

Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC₅₀) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origin of resistance to these drugs.