Inhibition of SARS-CoV 3CL protease by flavonoids

J Enzyme Inhib Med Chem. 2020 Dec;35(1):145-151. doi: 10.1080/14756366.2019.1690480.

Abstract

There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.

Keywords: FRET; SARS-CoV; SARS-CoV 3CLpro; flavonoid; inhibitory compounds.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / isolation & purification
  • Cysteine Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / chemical synthesis
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Molecular Structure
  • SARS Virus / drug effects*
  • SARS Virus / enzymology
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / isolation & purification
  • Viral Proteins / metabolism

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Flavonoids
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases

Grant support

This work was supported by the Basic Science Research Programmes, 2018R1D1A1B07050781 to DHS and 2018R1D1A1B07050942 to MK, funded by the National Research Foundation of Korea grant granted by the Ministry of Education, Science and Technology, Republic of Korea (MEST). S. Jo was supported by Brain Korea 21 (BK21) Project.