tetano
Editor, Senior Moderator
Nat Commun
. 2022 Feb 2;13(1):621.
doi: 10.1038/s41467-022-28113-1.
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
Ashleigh Shannon[SUP] 1 [/SUP], Véronique Fattorini[SUP] 1 [/SUP], Bhawna Sama[SUP] 1 [/SUP], Barbara Selisko[SUP] 1 [/SUP], Mikael Feracci[SUP] 1 [/SUP], Camille Falcou[SUP] 1 [/SUP], Pierre Gauffre[SUP] 1 [/SUP], Priscila El Kazzi[SUP] 1 [/SUP], Adrien Delpal[SUP] 1 [/SUP], Etienne Decroly[SUP] 1 [/SUP], Karine Alvarez[SUP] 1 [/SUP], Cécilia Eydoux[SUP] 1 [/SUP], Jean-Claude Guillemot[SUP] 1 [/SUP], Adel Moussa[SUP] 2 [/SUP], Steven S Good[SUP] 2 [/SUP], Paolo La Colla[SUP] 3 [/SUP], Kai Lin[SUP] 2 [/SUP], Jean-Pierre Sommadossi[SUP] 2 [/SUP], Yingxiao Zhu[SUP] 4 [/SUP], Xiaodong Yan[SUP] 4 [/SUP], Hui Shi[SUP] 4 [/SUP], François Ferron[SUP] 1 5 [/SUP], Bruno Canard[SUP] 6 7 [/SUP]
Affiliations
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[SUB]2[/SUB]-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.
. 2022 Feb 2;13(1):621.
doi: 10.1038/s41467-022-28113-1.
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
Ashleigh Shannon[SUP] 1 [/SUP], Véronique Fattorini[SUP] 1 [/SUP], Bhawna Sama[SUP] 1 [/SUP], Barbara Selisko[SUP] 1 [/SUP], Mikael Feracci[SUP] 1 [/SUP], Camille Falcou[SUP] 1 [/SUP], Pierre Gauffre[SUP] 1 [/SUP], Priscila El Kazzi[SUP] 1 [/SUP], Adrien Delpal[SUP] 1 [/SUP], Etienne Decroly[SUP] 1 [/SUP], Karine Alvarez[SUP] 1 [/SUP], Cécilia Eydoux[SUP] 1 [/SUP], Jean-Claude Guillemot[SUP] 1 [/SUP], Adel Moussa[SUP] 2 [/SUP], Steven S Good[SUP] 2 [/SUP], Paolo La Colla[SUP] 3 [/SUP], Kai Lin[SUP] 2 [/SUP], Jean-Pierre Sommadossi[SUP] 2 [/SUP], Yingxiao Zhu[SUP] 4 [/SUP], Xiaodong Yan[SUP] 4 [/SUP], Hui Shi[SUP] 4 [/SUP], François Ferron[SUP] 1 5 [/SUP], Bruno Canard[SUP] 6 7 [/SUP]
Affiliations
- PMID: 35110538
- DOI: 10.1038/s41467-022-28113-1
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[SUB]2[/SUB]-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.