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

Ashleigh Shannon, Véronique Fattorini, Bhawna Sama, Barbara Selisko, Mikael Feracci, Camille Falcou, Pierre Gauffre, Priscila El Kazzi, Adrien Delpal, Etienne Decroly, Karine Alvarez, Cécilia Eydoux, Jean-Claude Guillemot, Adel Moussa, Steven S. Good, Paolo Colla, Kai Lin, Jean-Pierre Sommadossi, Yingxiao Zhu, Xiaodong Yan, Hui Shi, François Ferron and Bruno Canard ()
Additional contact information
Ashleigh Shannon: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Véronique Fattorini: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Bhawna Sama: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Barbara Selisko: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Mikael Feracci: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Camille Falcou: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Pierre Gauffre: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Priscila El Kazzi: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Adrien Delpal: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Etienne Decroly: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Karine Alvarez: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Cécilia Eydoux: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Jean-Claude Guillemot: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Adel Moussa: Atea Pharmaceuticals, Inc.
Steven S. Good: Atea Pharmaceuticals, Inc.
Paolo Colla: Università degli Studi di Cagliari
Kai Lin: Atea Pharmaceuticals, Inc.
Jean-Pierre Sommadossi: Atea Pharmaceuticals, Inc.
Yingxiao Zhu: Wuxi Biortus Biosciences Co. Ltd
Xiaodong Yan: Wuxi Biortus Biosciences Co. Ltd
Hui Shi: Wuxi Biortus Biosciences Co. Ltd
François Ferron: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925
Bruno Canard: Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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-nsp82-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.

Date: 2022
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DOI: 10.1038/s41467-022-28113-1

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