Key result
AT-9010 inhibits SARS-CoV RNA synthesis by binding NiRAN and RdRp sites to block chain elongation.
Why the study?
The mechanism by which Coronaviridae viruses initiate viral RNA synthesis was unknown, and the structural basis for inhibition by AT-527 needed elucidation.
AT-527 inhibits SARS-CoV-1 and -2 RNA synthesis by binding to both the NiRAN and RdRp active sites of nsp12, providing a structural basis for its use as a COVID-19 treatment.
Answers are grounded in this paper and cite their sources.
May guide AT-527 development for COVID-19; animal data leave open human efficacy and safety.
Summary How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and −2 Ni dovirus R dRp- A ssociated N ucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA synthesis at the precise genome-poly(A) junction. The guanosine analogue 5’-triphosphate AT-9010 (prodrug: AT-527) tightly binds to the NiRAN and inhibits both nsp8-labeling and the initiation of RNA synthesis. A 2.98 Å resolution Cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-(nsp8) 2 /RNA/NTP quaternary complex shows AT-9010 simultaneously binds to both NiRAN and RdRp active site of nsp12, blocking their respective activities. AT-527 is currently in phase II clinical trials, and is a potent inhibitor of SARS-CoV-1 and −2, representing a promising drug for COVID-19 treatment.
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Shannon et al. (2021) studied SARS-CoV-1 and SARS-CoV-2 infection (COVID-19). AT-9010 (active triphosphate of AT-527) vs. Control (native nucleotides) was evaluated on Inhibition of nsp8-UMPylation and RNA synthesis initiation (IC50 0.87 µM). AT-9010, the active triphosphate of AT-527, inhibits SARS-CoV RNA synthesis by simultaneously binding to the NiRAN and RdRp active sites of nsp12, blocking nsp8-labeling and RNA chain elongation.
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