A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
2022
Shannon, Ashleigh | Fattorini, Véronique | Sama, Bhawna | Selisko, Barbara | Feracci, Mikael | Falcou, Camille | Gauffre, Pierre | El Kazzi, Priscila | Delpal, Adrien | Decroly, Etienne | Alvarez, Karine | Eydoux, Cécilia | Guillemot, Jean-Claude | Moussa, Adel | Good, Steven, | La Colla, Paolo | Lin, Kai | Sommadossi, Jean-Pierre | Zhu, Yingxiao | Yan, Xiaodong | Shi, Hui | Ferron, Francois | Canard, Bruno
International audience
Show more [+] Less [-]English. 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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