All Studies Meta Analysis

In Silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

Elkazzaz et al., Indian Journal of Pharmaceutical Education and Research, doi:10.5530/ijper.57.4.126

Oct 2023

Post
Facebook

Source PDF All Studies Meta AnalysisMeta

Vitamin A for COVID-19

42nd treatment shown to reduce risk in June 2023, now with p = 0.021 from 14 studies.

Lower risk for recovery and cases.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 treatments. c19early.org

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.

10 preclinical studies support the efficacy of vitamin A for COVID-19:

4 In Silico studies1-4

5 In Vitro studies1,5-8

1 In Vivo animal study9

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 function10-12. 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)7, is predicted to bind critical host and viral proteins for SARS-CoV-2 and may compensate for gene expression changes related to SARS-CoV-21-3, may be beneficial for COVID-19 via antiviral, anti-inflammatory, and immunomodulatory effects according to network pharmacology analysis4, reduces barrier compromise caused by TNF-α in Calu-3 cells6, inhibits mouse coronavirus replication9, may stimulate innate immunity by activating interferon responses in an IRF3-dependent manner (ATRA)9, may reduce excessive inflammation induced by SARS-CoV-21, shows SARS-CoV-2 antiviral activity In Vitro1,5,8, is effective against multiple SARS-CoV-2 variants in Calu-3 cells8, and inhibits the entry and replication of SARS-CoV-2 via binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease1.

Important missing comments or errors? Let us know.

1. 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.sciencedirect.com, doi.org.

2. Chakraborty et al., In-silico screening and in-vitro assay show the antiviral effect of Indomethacin against SARS-CoV-2, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105788.sciencedirect.com, doi.org.

3. 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.sciencedirect.com, doi.org.

4. Li et al., Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19, Aging, doi:10.18632/aging.103888.aging-us.com, doi.org.

5. 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.mdpi.com, doi.org.

6. 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.tandfonline.com, doi.org.

7. Tong et al., A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry, mBio, doi:10.1128/mbio.01485-22.asm.org, doi.org.

8. Morita et al., All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity, Viruses, doi:10.3390/v13081669.mdpi.com, doi.org.

9. Franco et al., Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK, Viruses, doi:10.3390/v16010140.mdpi.com, doi.org.

10. 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.mdpi.com, doi.org.

11. 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.mdpi.com, doi.org.

12. 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.europa.eu, doi.org.

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.

This Paper Vitamin A All

In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

Mahmoud Elkazzaz, Amr Ahmed, Yousry Esam Eldin Abo Amer, Tamer Haydara, Wafa Ali Eltayb, Mohammad Shahbaz Khan, Kunal Bhattacharya, Salma Alkhammash, Hadeer Mattar, Saba Beigh, Mohammed F Abo El Magd, Abdullah Haikal, Islem Abid, Amr S Abouzied, Dr Israa M Shamkh

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.

References

Agarwal, Mehrotra, An overview of molecular docking, JSM Chemistry

Ahmad, A comprehensive genomic study, mutation screening, phylogenetic and statistical analysis of SARS-CoV-2 and its variant omicron among different countries, Journal of Infection and Public Health

Babon, Varghese, Nicola, Inhibition of IL-6 family cytokines by SOCS3, Seminars in immunology, doi:10.1016/j.smim.2013.12.00426

Barrett, Human Peripheral Blood Mononuclear Cells Express High Levels of the Vitamin a Transport Protein, Stimulated by Retinoic Acid 6 (P19-004-19), Current Developments in Nutrition, doi:10.1093/cdn/nzz049.P19-004-19

Berry, Jin, Majumdar, Noy, Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses, Proceedings of the National Academy of Sciences USA

Bouillet, Sapin, Chazaud, Messaddeq, Décimo et al., Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein, Mechanisms of Development

Chassaing, Golzio, Odent, Lequeux, Vigouroux et al., Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia, Human Mutation

Chen, Clarke, Kim, Stowe, Kim et al., Structure of the STRA6 receptor for retinol uptake, Science, doi:10.1126/science.aad8266

Croker, Krebs, Zhang, Wormald, Willson et al., SOCS3 negatively regulates IL-6 signaling in vivo, Nature Immunology, doi:10.1038/ni931

Daniel, Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses, Proceedings of the National Academy of Sciences of the United States of America, doi:10.1073/pnas.1011115108

Devaprasad, Pandit, Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells, bioRxiv, doi:10.1101/2021.03.29.437515

Dias, Azevedo, Walter, Molecular docking algorithms, Current drug targets

Elkazzaz, Ahmed, Abo-Amer, Haydara, Eltayb et al., In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19, Indian J of Pharmaceutical Education and Research

Elkazzaz, Ahmed, Abo-Amer, Hydara, Haikal et al., In Silico Discovery of GPCRs and GnRHRs as Novel Binding Receptors of SARS-CoV-2 Spike Protein Could Explain Neuroendocrine Disorders in COVID-19, Vaccines

Elkazzaz, Discovery of the Retinol STRA6 Receptor as a Novel Binding Receptor for SARS-CoV-2 in COVID-19, Silico Research

Elkazzaz, STRA6 (vitamin A receptor), as a Novel binding receptor of COVID-19, Research square Preprints

Elkazzaz, STRA6 receptor-COVID-19

Fedders, Muenzner, Schupp, Retinol binding protein 4 and its membrane receptors: a metabolic perspective, Hormone Molecular Biology and Clinical Investigation

Goodman, Vitamin A and retinoids in health and disease, The New England Journal of Medicine, doi:10.1056/NEJM198404193101605

Henzler-Wildman, Kern, Dynamic personalities of proteins, Nature

Hornak, HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations, Proceedings of the National Academy of Sciences

Huang, Su, Theron, Wu, Lai et al., An interferon-gamma-related cytokine storm in SARS patients, Journal of Medical Virology, doi:10.1002/jmv.20255

Isken, Golczak, Oberhauser, Hunzelmann, Driever et al., RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome, Cell Metabolism

Johnson, Lewin, Ahmed, SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19, Frontiers in Immunology, doi:10.3389/fimmu.2020.582102

Karplus, Petsko, Molecular dynamics simulations in biology, Nature

Kawaguchi, Yu, Ter-Stepanian, Zhong, Cheng et al., Receptor-mediated cellular uptake mechanism that couples to intracellular storage, Sun HACS chemical biology

Kelly, Johannes Von Lintig, STRA6: role in cellular retinol uptake and efflux, Hepatobiliary surgery and nutrition, doi:10.3978/j.issn.2304-3881.2015.01.12

Kim, Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis, Immune Network, doi:10.4110/in.2018.18.e1

Kitakaze, Extracellular transglutaminase 2 induces myotube hypertrophy through G protein-coupled receptor 56, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research

Lindahl, Molecular dynamics simulations

Masi, Retinoic acid receptors: From molecular mechanisms to cancer therapy, Molecular Aspects of Medicine, doi:10.1016/j.mam.2014.12.003

Merad, Martin, Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nature Reviews Immunology, doi:10.1038/s41577-020-0331-4

Nair, Sugunan, Kumar, Anilkumar, Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population, PLoS One

Ng, Pasutto, Bardakjian, Wilson, Watson et al., A puzzle over several decades: eye anomalies with FRAS1 and STRA6 mutations in the same family, Clinical Genetics

Norseen, Hosooka, Hammarstedt, Yore, Kant et al., Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase-and toll-like receptor 4-dependent and retinol-independent mechanism, Mol Cell Biol, doi:10.1128/MCB.06193-11

Palczewski, Chemistry and biology of vision, Journal of Biological Chemistry, doi:10.1074/jbc.R111.301150

Pasutto, Sticht, Hammersen, Gillessen-Kaesbach, Fitzpatrick et al., Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation, American Journal of Human Genetics, doi:10.1086/512203

Pino-Lagos, Benson, Noelle, Retinoic acid in the immune system, Annals of the New York Academy of Sciences, doi:10.1196/annals.1443.017

Rather, Dhandare, Genome-Wide identification of doublesex and Mab-3-Related transcription factor (DMRT) genes in nile tilapia (Oreochromis niloticus), Biotechnology reports

Raverdeau, Mills, Modulation of T cell and innate immune responses by retinoic Acid, Journal of Immunology

Ross, Stephensen, Vitamin A and retinoids in antiviral responses, The FASEB Journal

Ruan, Yang, Wang, Jiang, Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China, Intensive Care Medicine, doi:10.1007/s00134-020-05991-x

Ruiz, Mark, Jacobs, Klopfenstein, Hu et al., Retinoid content, visual responses, and ocular morphology are compromised in the retinas of mice lacking the retinol-binding protein receptor, STRA6, Investigative Ophthalmology and Visual Science

Shamkh, Al-Majidi, Shntaif, Kai, Nh-Pham et al., Nontoxic and Naturally Occurring Active Compounds as Potential Inhibitors of Biological Targets in Liriomyza trifolii, International Journal of Molecular Sciences

Shirakami, Lee, Clugston, Blaner, Hepatic metabolism of retinoids and disease associations, Biochimica et Biophysica Acta, doi:10.1016/j.bbalip.2011.06.023

Tanoury, Piskunov, Egly, Vitamin A and retinoid signaling: Genomic and nongenomic effects, Journal of Lipid Research, doi:10.1194/jlr.R030833

Tepasse, Vollenberg, Fobker, Kabar, Schmidt et al., Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis, Nutrients, doi:10.3390/nu13072173

Ting Kam, Deng, Chen, Retinoic acid synthesis and functions in early embryonic development, Cell and Bioscience, doi:10.1186/2045-3701-2-11

West, Jr Extent of vitamin A deficiency among preschool children and women of reproductive age, Journal of Nutrition

Zafar, Genome wide identification, phylogeny, and synteny analysis of sox gene family in common carp (Cyprinus carpio), Biotechnology Reports

Zafar, Genome-Wide Identification and Expression Analysis of PPOs and POX Gene Families in the Selected Plant Species, Biosciences Biotechnology Research Asia

{ 'indexed': {'date-parts': [[2023, 10, 6]], 'date-time': '2023-10-06T04:44:53Z', 'timestamp': 1696567493027}, 'reference-count': 0, 'publisher': 'EManuscript Technologies', 'issue': '4', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'published-print': {'date-parts': [[2023, 10, 4]]}, 'DOI': '10.5530/ijper.57.4.126', 'type': 'journal-article', 'created': {'date-parts': [[2023, 10, 5]], 'date-time': '2023-10-05T11:50:57Z', 'timestamp': 1696506657000}, 'page': '1044-1052', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19', 'prefix': '10.5530', 'volume': '57', 'author': [ {'given': 'Mahmoud', 'family': 'Elkazzaz', 'sequence': 'first', 'affiliation': []}, {'given': 'Amr', 'family': 'Ahmed', 'sequence': 'additional', 'affiliation': []}, { 'given': 'Yousry Esam Eldin', 'family': 'Abo Amer', 'sequence': 'additional', 'affiliation': []}, {'given': 'Tamer', 'family': 'Haydara', 'sequence': 'additional', 'affiliation': []}, {'given': 'Wafa Ali', 'family': 'ELtayb', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mohammad Shahbaz', 'family': 'Khan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kunal', 'family': 'Bhattacharya', 'sequence': 'additional', 'affiliation': []}, {'given': 'Salma', 'family': 'Alkhammash', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hadeer', 'family': 'Mattar', 'sequence': 'additional', 'affiliation': []}, {'given': 'Saba', 'family': 'Beigh', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mohammed F', 'family': 'Abo El Magd', 'sequence': 'additional', 'affiliation': []}, {'given': 'Abdullah', 'family': 'Haikal', 'sequence': 'additional', 'affiliation': []}, {'given': 'Islem', 'family': 'Abid', 'sequence': 'additional', 'affiliation': []}, {'given': 'Amr S', 'family': 'Abouzied', 'sequence': 'additional', 'affiliation': []}, {'given': 'Israa M', 'family': 'Shamkh', 'sequence': 'additional', 'affiliation': []}], 'member': '3478', 'published-online': {'date-parts': [[2023, 10, 4]]}, 'container-title': 'Indian Journal of Pharmaceutical Education and Research', 'original-title': [], 'deposited': { 'date-parts': [[2023, 10, 5]], 'date-time': '2023-10-05T11:51:15Z', 'timestamp': 1696506675000}, 'score': 1, 'resource': {'primary': {'URL': 'https://ijper.org/article/2106'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 10, 4]]}, 'references-count': 0, 'journal-issue': { 'issue': '4', 'published-online': {'date-parts': [[2023, 10, 4]]}, 'published-print': {'date-parts': [[2023, 10, 4]]}}, 'URL': 'http://dx.doi.org/10.5530/ijper.57.4.126', 'relation': {}, 'ISSN': ['0019-5464'], 'subject': ['General Pharmacology, Toxicology and Pharmaceutics'], 'container-title-short': 'Ind. J. Pharm. Edu. Res', 'published': {'date-parts': [[2023, 10, 4]]}}

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0