7ED5

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

Summary for 7ED5

• Entry DOI: 10.2210/pdb7ed5/pdb
• EMDB information: 31061
• Descriptor: RNA-directed RNA polymerase, Non-structural protein 8, Non-structural protein 7, ... (8 entities in total)
• Functional Keywords: sars-cov-2, nsp12, niran, rdrp, at-9010, at-527, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 6
• Total formula weight: 189253.30

Authors

Shannon, A.,Fattorini, V.,Sama, B.,Selisko, B.,Feracci, M.,Falcou, C.,Gauffre, P.,El Kazzi, P.,Delpal, A.,Decroly, E.,Alvarez, K.,Eydoux, C.,Guillemot, J.-C.,Moussa, A.,Good, S.,Colla, P.,Lin, K.,Sommadossi, J.-P.,Zhu, Y.X.,Yan, X.D.,Shi, H.,Ferron, F.,Canard, B. (deposition date: 2021-03-15, release date: 2022-02-16, Last modification date: 2024-04-10)

Primary citation

Shannon, A.,Fattorini, V.,Sama, B.,Selisko, B.,Feracci, M.,Falcou, C.,Gauffre, P.,El Kazzi, P.,Delpal, A.,Decroly, E.,Alvarez, K.,Eydoux, C.,Guillemot, J.C.,Moussa, A.,Good, S.S.,La Colla, P.,Lin, K.,Sommadossi, J.P.,Zhu, Y.,Yan, X.,Shi, H.,Ferron, F.,Canard, B.
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase.
Nat Commun, 13:621-621, 2022

PubMed 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-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 nsp12 - known 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.

PubMed: 35110538
DOI: 10.1038/s41467-022-28113-1

Experimental method

ELECTRON MICROSCOPY (2.98 Å)