Potent Inhibition of SARS-CoV-2 nsp14 N 7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues

Rostom Ahmed-Belkacem (1) , Marcel Hausdorff (1) , Adrien Delpal (2) , Priscila Sutto-Ortiz (2) , Agathe M G Colmant (3) , Franck Touret (3) , Natacha S Ogando (4) , Eric J Snijder (4) , Bruno Canard (2) , Bruno Coutard (3, 5) , Jean-Jacques Vasseur (1) , Etienne Decroly (2) , Françoise Debart (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 AFMB - Architecture et fonction des macromolécules biologiques
3 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
4 LUMC - Leiden University Medical Center
5 UVE - Unité des Virus Emergents

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 (ΔT m ≈ 11 °C), and the best inhibitor demonstrated high selectivity for nsp14 over human RNA N7-MTase.

Domaines: Chimie analytique; Chimie; Chimie organique; Chimie thérapeutique

Rostom Ahmed-Belkacem, Marcel Hausdorff, Adrien Delpal, Priscila Sutto-Ortiz, Agathe M G Colmant, et al.. Potent Inhibition of SARS-CoV-2 nsp14 N 7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues. Journal of Medicinal Chemistry, 2022, 65 (8), pp.6231-6249. ⟨10.1021/acs.jmedchem.2c00120⟩. ⟨hal-03721688⟩