All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity

Viruses. 2021 Aug 23;13(8):1669. doi: 10.3390/v13081669.


The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC50) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.

Keywords: 3CL protease; FDA-approved drug; SARS-CoV-2; all-trans retinoic acid; antiviral efficacy; high throughput screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Cysteine Proteinase Inhibitors / pharmacology
  • DEAD Box Protein 58 / metabolism
  • High-Throughput Screening Assays
  • Humans
  • Receptors, Immunologic / metabolism
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • SARS-CoV-2 / physiology
  • Tretinoin / pharmacology*
  • Vero Cells
  • Virus Replication / drug effects


  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Receptors, Immunologic
  • Tretinoin
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
  • DDX58 protein, human
  • DEAD Box Protein 58