Structural Basis for Inhibition of the SARS‐CoV‐2 nsp16 by Substrate‐Based Dual Site Inhibitors

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 s...

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Published in:	ChemMedChem Vol. 19; no. 24; pp. e202400618 - n/a
Main Authors:	Kalnins, Gints, Rudusa, Laura, Bula, Anna L., Zelencova‐Gopejenko, Diana, Bobileva, Olga, Sisovs, Mihails, Tars, Kaspars, Jirgensons, Aigars, Jaudzems, Kristaps, Bobrovs, Raitis
Format:	Journal Article
Language:	English
Published:	Germany Wiley Subscription Services, Inc 16.12.2024 John Wiley and Sons Inc
Subjects:	Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Capping Catalytic Domain Coronaviruses COVID-19 Crystallography Crystallography, X-Ray Enzymatic activity Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Inhibitors Innate immunity Medicinal chemistry Methionine Methylation Methyltransferase Methyltransferases - antagonists & inhibitors Methyltransferases - chemistry Methyltransferases - metabolism Models, Molecular mRNA mRNA guanylyltransferase nsp16 Nucleotides S-Adenosylmethionine - chemistry S-Adenosylmethionine - metabolism SARS-CoV-2 SARS-CoV-2 - drug effects SARS-CoV-2 - enzymology Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Structural biology Substrate inhibition Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - metabolism Viral Regulatory and Accessory Proteins Medicinal chemistry SARS-CoV-2 nsp16 Structural biology Methyltransferase
ISSN:	1860-7179, 1860-7187, 1860-7187
Online Access:	Get full text
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Summary:	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. Structural information on the binding of S‐adenosyl methionine (SAM) analogues to SARS‐CoV‐2 nsp16 shows that targeting both the SAM and RNA binding sites simultaneously enhances inhibitory potential.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1860-7179 1860-7187 1860-7187
DOI:	10.1002/cmdc.202400618