What are NS5A inhibitors?
What are NS5A inhibitors? Non-structural protein 5A (NS5A) inhibitors are a direct-acting antiviral agent used to treat hepatitis C virus (HCV). The NS5A protein has a substantial role in viral replication, packaging, assembly and complex interactions with cellular functions.
Which of these antiviral drugs works by targeting NS5A?
Alisporivir, a host-targeting antiviral, is a cyclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction.
Is Harvoni a NS5A inhibitor?
Ledipasvir/sofosbuvir (Harvoni) Ledipasvir inhibits HCV NS5A protein, which is required for viral replication. Sofosbuvir is an inhibitor of HCV NS5B RNA-dependent polymerase. The oral combination is indicated for treatment of adults with chronic hepatitis C infection with genotype 1, 4, 5, or 6.
What is NS5A RASs?
Resistance-associated substitutions (RASs) are amino acid substitutions in HCV protein sequences that result in decreased antiviral efficacy of the HCV DAAs. Among the HCV RASs, the NS5A RASs were found to effectively modify and decrease treatment response to NS5A inhibitor-containing regimens.
What is non nucleoside polymerase inhibitor?
The non-nucleoside analogue inhibitors inhibit the polymerase activity in different ways, which depend on the allosteric site to which the inhibitor binds. Instead, by binding to RNA-dependent RNA polymerase, they inhibit polymerase activity by inhibiting conformational changes which are necessary for NS5B activity.
What is ribavirin MOA?
The drug inhibits the activity of the enzyme RNA dependent RNA polymerase, due to its resemblence to building blocks of the RNA molecules. Ribavirin is reported to have several mechanism of actions that lead to inhibition of viral RNA and protein synthesis.
Are there any second generation NS5A inhibitors available?
Second-generation NS5A inhibitors with improved barrier to resistance will soon reach early clinical development. Daclatasvir, a pangenotypic NS5A inhibitor, is approved in the European Union (2014) for use as part of HCV combination therapy and in the USA (2015) for use specifically with sofosbuvir for treatment of HCV genotype 3.
How are NS5A inhibitors used to treat HCV?
NS5A inhibitors bind to domain I of the NS5A protein and block its ability to regulate HCV replication within the replication complex, through an as-yet-unclear mechanism.
Is the barrier to resistance for NS5A inhibitors high?
NS5A inhibitors are potent and have pangenotypic coverage (Table 5.2 ). The barrier to resistance of first-generation molecules is low for HCV subtype 1a, high for other genotypes/subtypes ( Brown et al., 2010; Gao et al., 2010; Lawitz, Gruener, et al., 2011; Nettles et al., 2008, 2010; Wang et al., 2012 ).
How does NS34 interact with other protease inhibitors?
Simeprevir: This NS34 A HCV protease inhibitor has complex interactions with antiretroviral medications because it is a substrate and an inhibitor of CYP3A4 and p-glycoprotein. In addition, simeprevir inhibits the OATP1B1/3 drug transporter.