A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry
Tong et al.
, A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry
, mBio, doi:10.1128/mbio.01485-22 (In Vitro)
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.
Tong et al., 13 Jul 2022, China, peer-reviewed, 14 authors.
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In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: RESEARCH ARTICLE
A Retinol Derivative Inhibits SARS-CoV-2 Infection by
Interrupting Spike-Mediated Cellular Entry
Liangqin Tong,a,b Lin Wang,a Shumin Liao,c,d Xiaoping Xiao,a Jing Qu,e Chunli Wu,e Yibin Zhu,a Wanbo Tai,b Yanhong Huang,f,g
Penghua Wang,h Liang Li,f,g Renli Zhang,e Ye Xiang,a Gong Chenga,b
Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure and Beijing Advanced Innovation Center for Structural Biology,
School of Medicine, Tsinghua University, Beijing, China
Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China
Department of Otolaryngology, the Seventh Afﬁliated Hospital of Sun Yat-sen University, Shenzhen, China
Department of Thoracic Surgery, the Seventh Afﬁliated Hospital of Sun Yat-sen University, Shenzhen, China
Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
Department of Immunology, School of Medicine, the University of Connecticut Health Center, Farmington, Connecticut, USA
Liangqin Tong, Lin Wang and Shumin Liao contributed equally to this work. Author order was determined by the duration worked on this project.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the
etiological agent of the global pandemic and life-threatening coronavirus disease
2019 (COVID-19). 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 SARSCoV-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..
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