Abstract
The SARS-CoV-2 helicase NSP13 is a highly conserved and essential component of the viral replication machinery, making it a promising target for antiviral drug development. Here, we present the 2 Å resolution crystal structure of NSP13 bound to the natural flavonoid myricetin, revealing a conserved allosteric binding site. Guided by these structural findings, a virtual screening campaign identified the caffeic acid derivatives rosmarinic acid and chlorogenic acid as potential novel natural inhibitors, which were experimentally validated to inhibit RNA-unwinding activity. This study provides structural insights that could support ongoing drug-discovery efforts targeting NSP13 in SARS-CoV-2 and other coronaviruses with pandemic potential.
Keywords:
NSP13 helicase; SARS-CoV-2; antiviral drug development; caffeic acid derivatives; myricetin; natural inhibitors; virtual screening.
open access.
MeSH terms
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Allosteric Site
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Antiviral Agents* / chemistry
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Antiviral Agents* / pharmacology
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Binding Sites
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Chlorogenic Acid / chemistry
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Chlorogenic Acid / pharmacology
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Cinnamates / chemistry
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Cinnamates / pharmacology
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Crystallography, X-Ray
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Depsides / chemistry
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Depsides / pharmacology
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Drug Discovery
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Flavonoids* / chemistry
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Flavonoids* / metabolism
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Flavonoids* / pharmacology
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Humans
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Methyltransferases
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Models, Molecular
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Protein Binding
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Protein Conformation
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RNA Helicases* / antagonists & inhibitors
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RNA Helicases* / chemistry
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RNA Helicases* / metabolism
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Rosmarinic Acid
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SARS-CoV-2* / drug effects
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SARS-CoV-2* / enzymology
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Viral Nonstructural Proteins* / antagonists & inhibitors
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Viral Nonstructural Proteins* / chemistry
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Viral Nonstructural Proteins* / metabolism
Substances
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myricetin
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Viral Nonstructural Proteins
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RNA Helicases
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Flavonoids
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Antiviral Agents
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Nsp13 protein, SARS-CoV
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Cinnamates
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Depsides
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Chlorogenic Acid
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Rosmarinic Acid
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Methyltransferases