Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance

Abstract

The era of interferon-free antiviral treatments for hepatitis C virus infection has arrived. With increasing numbers of approved antivirals, evaluating all parameters that may influence response is necessary to choose optimal combinations for treatment success. Targeting NS5A has become integral in antiviral combinations in clinical development. Daclatasvir and ledipasvir belong to the NS5A inhibitor class, which directly target the NS5A protein. Alisporivir, a host-targeting antiviral, is a cyclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction. Resistance to daclatasvir and ledipasvir differs from alisporivir, with mutations arising in NS5A domains I and II, respectively. Combining these two classes acting on distinct NS5A domains represents an attractive strategy for potentially effective interferon-free treatments for chronic hepatitis C infection.

Figure 1

Two targets, one protein. Data from resistance mutations mapping reveal that daclatasvir or ledipasvir target domain I of NS5A while alisporivir leads to mutations in domain II of NS5A.