Journal Article

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

Selisko, Barbara, Falcou, Camille, Feracci, Mikael, El Kazzi, Priscila, Ferron, Francois, Shannon, Ashleigh, Yan, Xiaodong, Gauffre, Pierre, Delpal, Adrien, Moussa, Adel, Good, Steven, S, Lin, Kai, European Virus Bioinformatics Center [Jena], Università degli Studi di Cagliari = University of Cagliari = Université de Cagliari (UniCa), Zhu, Yingxiao, Wuxi Biortus Biosciences, Sommadossi, Jean-Pierre, Alvarez, Karine, Eydoux, Cécilia, Architecture et fonction des macromolécules biologiques (AFMB) ; Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Shi, Hui, La Colla, Paolo, Fattorini, Véronique, Canard, Bruno, Sama, Bhawna, Decroly, Etienne, Guillemot, Jean-Claude, Atea Pharmaceuticals

2022

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 101/28 / 631/45/607/1167 / 631/535/1258/1259 / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Binding / Biochemistry / Biochemistry, Molecular Biology / Biophysics / Clinical trials / Coronaviruses / COVID-19 / COVID-19 - virology / Cryoelectron Microscopy / DNA-directed RNA polymerase / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Guanine / Guanosine Monophosphate - analogs & derivatives / Guanosine Monophosphate - chemistry / Guanosine Monophosphate - pharmacology / Humanities and Social Sciences / Humans / Life Sciences / multidisciplinary / Nucleotides / Phosphoramides - chemistry / Phosphoramides - pharmacology / Ribose / RNA polymerase / RNA-Dependent RNA Polymerase - antagonists & inhibitors / RNA-Dependent RNA Polymerase - chemistry / RNA-Dependent RNA Polymerase - genetics / RNA-Dependent RNA Polymerase - metabolism / RNA-directed RNA polymerase / SARS-CoV-2 - chemistry / SARS-CoV-2 - drug effects / SARS-CoV-2 - enzymology / SARS-CoV-2 - genetics / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Transcription / Viral diseases / Viral Proteins - antagonists & inhibitors / Viral Proteins - genetics / Viral Proteins - metabolism