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

• DOI: 10.1038/s41467-022-28113-1
• Publication Date: 2022-02-02T11:06:03Z
• Authors: 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 Guill...; Adel Moussa; Steven S. Good; Paolo La Colla; Kai Lin; Jean-Pierre Somma...; Yingxiao Zhu; Xiaodong Yan; Hui Shi; François Ferron; Bruno Canard
• Keywords: Mechanism of Action

Abstract The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, is converted into its triphosphate form, AT-9010, that presumably targets viral RNA-dependent RNA polymerase (RdRp, nsp12), incorporation RNA. Here we report 2.98 Å cryo-EM structure SARS-CoV-2 nsp12-nsp7-nsp8 -RNA complex, showing AT-9010 bound at three sites nsp12. In RdRp active-site, one incorporated 3′ end product strand. Its modified ribose group (2′-fluoro, 2′-methyl) prevents correct alignment incoming NTP, this case second causing immediate termination synthesis. third to N-terminal domain nsp12 - known as NiRAN. contrast native NTPs, flipped orientation with guanine base unexpectedly occupying previously unnoticed cavity. outcompetes all nucleotides NiRAN binding, inhibiting nucleotidyltransferase activity. dual mechanism action both and active research avenue