Bemnifosbuvir (AT-527): A Comprehensive Monograph on a Dual-Target Antiviral from Hepatitis C to the COVID-19 Pandemic

Executive Summary

Bemnifosbuvir, also known as AT-527, is an orally bioavailable, investigational small molecule developed by Atea Pharmaceuticals as a direct-acting antiviral agent. Structurally, it is a guanosine nucleotide "double prodrug" designed for efficient intracellular delivery of its active triphosphate metabolite, AT-9010. This active form targets the highly conserved RNA-dependent RNA polymerase (RdRp) enzyme, a critical component of the replication machinery for many single-stranded RNA viruses.

The drug's development has followed a dual trajectory, initially showing exceptional promise against the Hepatitis C Virus (HCV). In early-phase clinical trials, bemnifosbuvir demonstrated potent, pan-genotypic antiviral activity, inducing rapid and profound reductions in HCV RNA viral load in patients with and without cirrhosis. This success established a strong scientific foundation for its potential as a cornerstone of future HCV combination therapies.

With the onset of the COVID-19 pandemic, bemnifosbuvir was rapidly repurposed for investigation against SARS-CoV-2. Preclinical studies revealed a unique dual mechanism of action against the coronavirus, inhibiting not only the canonical RdRp active site but also the novel NiRAN (Nidovirus RdRp-Associated Nucleotidyltransferase) domain. This dual-target engagement, combined with superior in vitro potency compared to other oral antivirals, positioned bemnifosbuvir as a leading candidate and led to a major strategic collaboration with Roche.