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A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry

Tong et al., mBio, doi:10.1128/mbio.01485-22
Jul 2022  
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Vitamin A for COVID-19
12th treatment shown to reduce risk in January 2021
*, now known with p = 0.045 from 12 studies.
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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 study showing all-trans retinoic acid, a vitamin A derivative, has potent antiviral activity against SARS-CoV-2 in both human cell lines and human organoids of the lower respiratory tract.
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.
Tong et al., 13 Jul 2022, China, peer-reviewed, 14 authors. Contact:,,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin AAll
A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry
Liangqin Tong, Lin Wang, Shumin Liao, Xiaoping Xiao, Jing Qu, Chunli Wu, Yibin Zhu, Wanbo Tai, Yanhong Huang, Penghua Wang, Liang Li, Renli Zhang, Ye Xiang, Gong Cheng
mBio, doi:10.1128/mbio.01485-22
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 . Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all-trans retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. IMPORTANCE Retinoids, a group of compounds including vitamin A and its active metabolite all-trans retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.
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