Atea Pharmaceuticals, Inc. announced that new data highlighting bemnifosbuvir (AT-527) were published in the peer-reviewed journal, Nature Communications, in an article titled, “A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase.” The published data demonstrate that bemnifosbuvir's unique mechanism of action, with dual targets consisting of chain termination (RdRp) and nucleotityltransferase (NiRAN) inhibition, has the potential to create a high barrier to resistance with broad antiviral activity across SARS-CoV-2 variants of concern. Bemnifosbuvir is an orally administered, non-mutagenic, direct-acting antiviral agent derived from Atea's purine nucleotide prodrug platform. In Phase 2 clinical trials, bemnifosbuvir has demonstrated rapid and sustained antiviral activity in high-risk patients with COVID-19 and has been shown to be generally safe and well tolerated.

Bemnifosbuvir targets SARS-CoV-2 RNA polymerase (nsp12), a highly conserved gene that is unlikely to change as the virus mutates and new variants emerge. This gene is responsible for both replication and transcription of SARS-CoV-2. The inhibition of RNA polymerase has been shown in vitro to effectively block production of coronavirus. In addition, in vitro data confirm that bemnifosbuvir is active against all variants of concern or interest that have been tested.

The SARS-CoV-2 nsp12 RNA polymerase has two functional domains, the well-established C-terminal RNA-dependent RNA polymerase (RdRp) and the previously uncharacterized N-terminal nidovirus RdRp associated NiRAN. To further detail the mechanism of action of bemnifosbuvir, researchers obtained a 2.9 Å cryo-EM structure of nsp12 with its cofactors nsp7 and nsp8, an RNA template, and AT-9010, the active triphosphate metabolite of bemnifosbuvir. These new data demonstrate that the SARS-CoV-2 nsp12-nsp7-(nsp8)2 minimal replication transcription complex can promote two reactions essential to virus growth: grafting nucleotides onto viral proteins nsp8 and nsp9 by means of the NiRAN domain and de novo synthesis of dinucleotide primers by RdRp in a NiRAN-independent fashion.

Both pathways are inhibited by AT-9010, the triphosphate metabolite of bemnifosbuvir, thus supporting bemnifosbuvir's unique dual mechanism of action for the treatment of COVID-19.