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

Morita et al., Viruses, doi:10.3390/v13081669
Aug 2021  
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Vitamin A for COVID-19
12th treatment shown to reduce risk in January 2021
*, now known with p = 0.031 from 13 studies.
Lower risk for recovery and viral clearance.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
In Vitro and In Silico study showing that all-trans retinoic acid is a potent SARS-CoV-2 3CLpro inhibitor, inhibits SARS-CoV-2 replication in VeroE6/TMPRSS2 cells, and is effective against alpha, beta, gamma, and delta variants in Calu-3 cells.
10 preclinical studies support the efficacy of vitamin A for COVID-19:
Vitamin A has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function EFSA, Galmés, Galmés (B). Vitamin A has potent antiviral activity against SARS-CoV-2 in both human cell lines and human organoids of the lower respiratory tract (active metabolite all-trans retinoic acid, ATRA) Tong, is predicted to bind critical host and viral proteins for SARS-CoV-2 and may compensate for gene expression changes related to SARS-CoV-2 Chakraborty, Huang, Pandya, may be beneficial for COVID-19 via antiviral, anti-inflammatory, and immunomodulatory effects according to network pharmacology analysis Li, reduces barrier compromise caused by TNF-α in Calu-3 cells DiGuilio, inhibits mouse coronavirus replication Franco, may stimulate innate immunity by activating interferon responses in an IRF3-dependent manner (ATRA) Franco, may reduce excessive inflammation induced by SARS-CoV-2 Huang, shows SARS-CoV-2 antiviral activity In Vitro Huang, Moatasim, Morita, is effective against multiple SARS-CoV-2 variants in Calu-3 cells Morita, and inhibits the entry and replication of SARS-CoV-2 via binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease Huang.
Morita et al., 23 Aug 2021, peer-reviewed, 9 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin AAll
All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity
Takeshi Morita, Kei Miyakawa, Sundararaj Stanleyraj Jeremiah, Yutaro Yamaoka, Mitsuru Sada, Tomoko Kuniyoshi, Jinwei Yang, Hirokazu Kimura, Akihide Ryo
Viruses, 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 (IC 50 ) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC 50 = 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.
Supplementary Materials: The following are available online at 10.3390/v13081669/s1, Figure S1 : The comparison of FRET and AlphaScreen, Figure S2 : Graphical determination of the type pf inhibition, Figure S3 : Cytotoxicity of ATRA, Figure S4 : Protein expression in ATRA treated Calu-3 cells during SARS-CoV-2 infection, Figure S5 : Amino acid sequence alignment of 3CLpro, Table S1 : The list of compounds screened by the enzyme assay. Conflicts of Interest: The authors declare no competing financial interest. Y.Y. is a current employee of Kanto Chemical Co., Inc. T.K. and J.Y. are a current employee of TOKIWA Phytochemical Co., Ltd.
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