Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2'-O-Methylation of Viral RNA.
Viruses
; 12(5)2020 05 10.
Article
in English
| MEDLINE | ID: covidwho-1121808
ABSTRACT
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2'-O-methyltransferase (2'-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2'-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2'-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique "activating surface" between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10-drug complexes, we considered their pharmacological overlapping with functional modules of the virus-host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2'-O-methylation.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pneumonia, Viral
/
RNA, Viral
/
RNA Processing, Post-Transcriptional
/
Coronavirus Infections
/
Immune Evasion
/
Betacoronavirus
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Year:
2020
Document Type:
Article
Affiliation country:
V12050525
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