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A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

Abstract : The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp8 2-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3′ end of the RNA product strand. Its modified ribose group (2′-fluoro, 2′-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19.
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https://hal.archives-ouvertes.fr/hal-03572811
Contributor : François Ferron Connect in order to contact the contributor
Submitted on : Monday, February 14, 2022 - 1:55:09 PM
Last modification on : Friday, May 6, 2022 - 2:56:02 PM
Long-term archiving on: : Sunday, May 15, 2022 - 6:56:23 PM

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Ashleigh Shannon, Véronique Fattorini, Bhawna Sama, Barbara Selisko, Mikael Feracci, et al.. A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Nature Communications, Nature Publishing Group, 2022, 13, ⟨10.1038/s41467-022-28113-1⟩. ⟨hal-03572811⟩

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