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Potent Inhibition of SARS-CoV-2 nsp14 N7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues.
Ahmed-Belkacem, Rostom; Hausdorff, Marcel; Delpal, Adrien; Sutto-Ortiz, Priscila; Colmant, Agathe M G; Touret, Franck; Ogando, Natacha S; Snijder, Eric J; Canard, Bruno; Coutard, Bruno; Vasseur, Jean-Jacques; Decroly, Etienne; Debart, Françoise.
  • Ahmed-Belkacem R; IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, cedex 5, France.
  • Hausdorff M; IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, cedex 5, France.
  • Delpal A; AFMB, University of Aix-Marseille, CNRS, 13288 Marseille, cedex 9, France.
  • Sutto-Ortiz P; AFMB, University of Aix-Marseille, CNRS, 13288 Marseille, cedex 9, France.
  • Colmant AMG; IHU Méditerranée Infection, Unité Virus Emergents, University of Aix-Marseille, IRD 190, INSERM 1207, 13005 Marseille, France.
  • Touret F; IHU Méditerranée Infection, Unité Virus Emergents, University of Aix-Marseille, IRD 190, INSERM 1207, 13005 Marseille, France.
  • Ogando NS; Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
  • Snijder EJ; Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
  • Canard B; AFMB, University of Aix-Marseille, CNRS, 13288 Marseille, cedex 9, France.
  • Coutard B; IHU Méditerranée Infection, Unité Virus Emergents, University of Aix-Marseille, IRD 190, INSERM 1207, 13005 Marseille, France.
  • Vasseur JJ; IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, cedex 5, France.
  • Decroly E; AFMB, University of Aix-Marseille, CNRS, 13288 Marseille, cedex 9, France.
  • Debart F; IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, cedex 5, France.
J Med Chem ; 65(8): 6231-6249, 2022 04 28.
Article in English | MEDLINE | ID: covidwho-1867997
ABSTRACT
Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and synthesis of nucleoside-derived inhibitors against the SARS-CoV-2 nsp14 (N7-guanine)-methyltransferase (N7-MTase) that catalyzes the transfer of the methyl group from the S-adenosyl-l-methionine (SAM) cofactor to the N7-guanosine cap. Seven compounds out of 39 SAM analogues showed remarkable double-digit nanomolar inhibitory activity against the N7-MTase nsp14. Molecular docking supported the structure-activity relationships of these inhibitors and a bisubstrate-based mechanism of action. The three most potent inhibitors significantly stabilized nsp14 (ΔTm ≈ 11 °C), and the best inhibitor demonstrated high selectivity for nsp14 over human RNA N7-MTase.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c00120

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c00120