Structural basis for inhibition of the SARS-CoV-2 nsp16 by substrate-based dual site inhibitors.

Autor: Kalnins G; Latvian Biomedical Research and Study Centre, Structural Biology Group, LATVIA., Rudusa L; Latvian Institute of Organic Synthesis, Laboratory of structural biology and drug design, LATVIA., Bula A; Latvian Institute of Organic Synthesis, Laboratory of structural biology and drug design, LATVIA., Zelencova-Gopejenko D; Latvian Institute of Organic Synthesis, Laboratory of structural biology and drug design, LATVIA., Bobileva O; Latvian Institute of Organic Synthesis, Organic Synthesis Methodology Group, LATVIA., Sisovs M; Latvian Biomedical Research and Study Centre, Structural Biology Group, LATVIA., Tars K; Latvian Biomedical Research and Study Centre, Structural Biology Group, LATVIA., Jirgensons A; Latvian Institute of Organic Synthesis, Organic Synthesis Methodology Group, LATVIA., Jaudzems K; Latvian Institute of Organic Synthesis, Laboratory of structural biology and drug design, LATVIA., Bobrovs R; Latvian Institute of Organic Synthesis, Laboratory of structural biology and drug design, Aizkraukles 21, LV1006, Riga, LATVIA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Sep 11, pp. e202400618. Date of Electronic Publication: 2024 Sep 11.
DOI: 10.1002/cmdc.202400618
Abstrakt: Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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