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Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne

Mana Murae1,2, Shota Sakai1, Non Miyata1

  • 1Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases.

Biological & Pharmaceutical Bulletin
|May 1, 2024
PubMed

Insights

A new compound, Nat-20(S)-yne, inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking viral entry and decreasing cholesterol biosynthesis. This cholesterol derivative shows potential as a novel antiviral therapy for COVID-19.

Area of Science:

  • Biochemistry
  • Virology
  • Drug Discovery

Background:

  • Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, remains a global health threat requiring new antiviral treatments.
  • Cholesterol derivatives, like 25-hydroxycholesterol, demonstrate antiviral properties against SARS-CoV-2.
  • Viral entry involves the fusion of the viral envelope with host membranes, mediated by spike (S) glycoproteins.

Purpose of the Study:

  • To identify novel cholesterol derivatives with antiviral activity against SARS-CoV-2.
  • To investigate the mechanism of action of a newly identified compound, Nat-20(S)-yne, focusing on its effect on viral entry and replication.

Main Methods:

  • Screening of cholesterol derivatives to identify compounds inhibiting SARS-CoV-2 S protein-mediated membrane fusion.
  • Syncytium formation assays to evaluate inhibition of viral entry.
  • In vitro assays using SARS-CoV-2 pseudoviruses and intact SARS-CoV-2 to assess dose-dependent inhibitory activity.
  • Analysis of the effect on de novo cholesterol biosynthesis and plasma membrane cholesterol content.

Main Results:

  • Nat-20(S)-yne was identified as an inhibitor of SARS-CoV-2 S protein-dependent membrane fusion.
  • The compound demonstrated dose-dependent inhibition of SARS-CoV-2 pseudovirus entry and intact virus infection.
  • Inhibition was more pronounced against Delta and Wuhan strains compared to Omicron strains, correlating with their cell entry mechanisms.
  • Nat-20(S)-yne specifically inhibited de novo cholesterol biosynthesis, leading to reduced plasma membrane cholesterol and suppressed viral infection, without affecting the S protein-ACE2 interaction.

Conclusions:

  • Nat-20(S)-yne represents a novel antiviral agent targeting SARS-CoV-2 entry via inhibition of cholesterol biosynthesis.
  • Its unique mechanism of action suggests potential as a therapeutic candidate for COVID-19, particularly against strains entering via plasma membrane fusion.
Keywords:
26,27-dinorcholest-5-en-24-yne-3β,20-diol (Nat-20(S)-yne)antiviralcholesterolcholesterol biosynthesiscoronavirus disease 2019 (COVID-19)severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

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