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All-trans retinoic acid acts as a dual-purpose inhibitor of SARS-CoV-2 infection and inflammation

Huang et al., Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2024.107942
Jan 2024  
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Vitamin A for COVID-19
39th treatment shown to reduce risk in June 2023
*, now known with p = 0.045 from 12 studies.
Lower risk for recovery.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
In Vitro and In Silico study showing that all-trans retinoic acid (an active metabolite of vitamin A) inhibits the entry and replication of SARS-CoV-2 by binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease, and reduces excessive inflammation induced by SARS-CoV-2.
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.
Huang et al., 3 Jan 2024, peer-reviewed, 7 authors. Contact:,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin AAll
A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants
Chong Huang, Huiping Shuai, Jingxin Qiao, Yuxin Hou, Rui Zeng, Anjie Xia, Lingwan Xie, Zhen Fang, Yueyue Li, Chaemin Yoon, Qiao Huang, Bingjie Hu, Jing You, Baoxue Quan, Xiu Zhao, Nihong Guo, Shiyu Zhang, Ronggang Ma, Jiahao Zhang, Yifei Wang, Ruicheng Yang, Shanshan Zhang, Jinshan Nan, Haixing Xu, Falu Wang, Jian Lei, Hin Chu, Shengyong Yang
Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01392-w
Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (M pro ). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance M pro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.
AUTHOR CONTRIBUTIONS S.Y., H.C., and J.L. conceived research; and C.H. performed the drug design; C.H., A.X., and Z.F. with the assistance of Q.H., J.Y., B.Q., N.G., S.Z., R.M., J.Z., S.Z., J.N., H.X., and F.W. performed the chemical synthesis; R.Z., L.X., J.Q., and X.Z. performed gene expression, protein purification and crystallization experiments; R.Z., L.X., and J.L. determined the crystal structures; J.Q. and Y.L. performed high-throughput screening, enzymatic activity and inhibition assays, IC 50 measurements, DSF assays, cytotoxicity assays and in vivo toxicity assays; H.S., Y.H., C.Y., and B.H. performed in vitro and in vivo antiviral assays; S.Y., J.L., and H.C. with the assistance of C.H., H.S., J.Q., and R.Z. wrote and revised the manuscript. All authors have read and approved the article. ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available at Competing interests: All authors declared no competing interests. S.Y. is the member of editorial board, he has not been involved in the process of the manuscript handling.
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