In Silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19
et al., Indian Journal of Pharmaceutical Education and Research, doi:10.5530/ijper.57.4.126, Oct 2023
Vitamin A for COVID-19
48th treatment shown to reduce risk in
June 2023, now with p = 0.0052 from 15 studies.
No treatment is 100% effective. Protocols
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210+ treatments. c19early.org
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In silico study analyzing the potential role of the STRA6 vitamin A receptor in SARS-CoV-2 infection. Authors found that the SARS-CoV-2 spike protein binds strongly to STRA6, suggesting potential use in addition to ACE2. Binding to STRA6 could disrupt vitamin A uptake and explain some COVID-19 complications like immune suppression. The authors propose restoring balance between STRA6 and ACE2 as a promising therapeutic target.
11 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 function11-13.
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)8, is predicted to bind critical host and viral proteins for SARS-CoV-2 and may compensate for gene expression changes related to SARS-CoV-22-4, may be beneficial for COVID-19 via antiviral, anti-inflammatory, and immunomodulatory effects according to network pharmacology analysis5, reduces barrier compromise caused by TNF-α in Calu-3 cells7, inhibits mouse coronavirus replication10, may stimulate innate immunity by activating interferon responses in an IRF3-dependent manner (ATRA)10, may reduce excessive inflammation induced by SARS-CoV-22, shows SARS-CoV-2 antiviral activity In Vitro2,6,9 , is effective against multiple SARS-CoV-2 variants in Calu-3 cells9, and inhibits the entry and replication of SARS-CoV-2 via binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease2.
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Huang et al., All-trans retinoic acid acts as a dual-purpose inhibitor of SARS-CoV-2 infection and inflammation, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2024.107942.
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Pandya et al., Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951.
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Li et al., Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19, Aging, doi:10.18632/aging.103888.
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Moatasim et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms, doi:10.3390/microorganisms11112777.
7.
DiGuilio et al., The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function, Experimental Lung Research, doi:10.1080/01902148.2023.2193637.
8.
Tong et al., A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry, mBio, doi:10.1128/mbio.01485-22.
9.
Morita et al., All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity, Viruses, doi:10.3390/v13081669.
10.
Franco et al., Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK, Viruses, doi:10.3390/v16010140.
11.
Galmés et al., Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations, Nutrients, doi:10.3390/nu14112254.
12.
Galmés (B) et al., Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, Nutrients, doi:10.3390/nu12092738.
13.
EFSA, Scientific Opinion on the substantiation of health claims related to vitamin A and cell differentiation (ID 14), function of the immune system (ID 14), maintenance of skin and mucous membranes (ID 15, 17), maintenance of vision (ID 16), maintenance of bone (ID 13, 17), maintenance of teeth (ID 13, 17), maintenance of hair (ID 17), maintenance of nails (ID 17), metabolism of iron (ID 206), and protection of DNA, proteins and lipids from oxidative damage (ID 209) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2009.1221.
Elkazzaz et al., 4 Oct 2023, peer-reviewed, 15 authors.
Contact: israamshamkh@gmail.com.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19
Indian Journal of Pharmaceutical Education and Research, doi:10.5530/ijper.57.4.126
A global pandemic of pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, at the end of 2019. Although, the ACE2 receptor has been demonstrated to be the main entry receptor of COVID-19, but our docking analysis, predicted and discovered a novel receptor termed STRA 6 that may play a critical role in the pathogenicity of COVID-19. STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid jm6 (STRA 6) was the first protein to be identified in a novel category of proteins, cytokine signaling transporters, due to its ability to function as both a cell surface receptor and a membrane protein that binds to retinol binding protein facilitating cellular uptake of retinol. The primary ligand of STRA6 (vitamin/retinol) was shown to be drastically reduced during COVID-19 infection, which agrees with our findings. We analyze the STRA6 and ACE2 receptor networks to predict the specific association among certain other proteins which might rely on similar functionality. Molecular docking showed a high affinity between the Spike protein with STRA6, the docking score of COVID-19 spike protein with STRA6 (-354.68) kcal/mol was higher than the docking score of spike protein with ACE2 (-341.21) kcal/mol. Results of MD simulations revealed significant stability of the spike protein with STRA6 up to 100 ns. SARS-CoV-2 spike protein binds strongly and directly to STRA6. Which are highly expressed in Lymphatic system and Immune cells. This study paves the way towards understanding the complex mechanism of existing of covid-19 infection complications such as immune suppression and ineffective RIG-I pathway. Restoring the balance between the STRA6 and ACE2 in the context of spike protein RBD may be promising target in SARS CoV-2 Pathogenesis and may reveal new drug targets for new variants of COVID-19.
ACKNOWLEDGEMENT The authors extend their appreciation to the Researchers Supporting Project number (RSPD2023R745), King Saud University, Riyadh, Saudi Arabia.
CONFLICT OF INTEREST The authors declare that there is no conflict of interest.
AUTHORS' CONTRIBUTIONS Mahmoud Elkazzaz, Israa M. Shamkh and Amr Ahmed: Conceptualization Mahmoud Elkazzaz, Israa M. Shamkh, Amr Ahmed, Abdullah Haikal, data curation, formal analysis, investigation, methodology, software, validation, visualization, writing -original draft, writing -review, editing, validation, visualization, writing -original draft, writing -review and editing.
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