STRA6 (vitamin A receptor), as a Novel binding receptor of COVID-19 (A breakthrough)

Abstract

BackgroundA 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 STRA6 that may play a critical role in the pathogenicity of COVID-19 and explain the common pre and post COVID-19 symptoms with unknown etiology. STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid jm6 (STRA6) 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.Methods The STRA6 receptor protein were submitted to the server for functional interaction associated network between partners for the STRING (Research Online of Interacting Genes/Proteins Data Basis version 10.0)13 .Docking study of each Spike -ACE 2 and STRA6 receptor protein were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Spike -ACE 2 and STRA6 receptor protein is retrieved form the PDB https://www.rcsb.org/ with accession number (7DMU , 5sy1)ResultsSurprisingly, our molecular docking based analysis showed that spike protein Receptor Binding Domain(RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor. STRA6 receptor is a membrane receptor responsible for signaling and transporting of Vitamin A(Retinol) from plasma retinol binding protein (RBP) to our cells. In an outstanding manner, COVID-19 Spike protein exhibited high docking score with human STRA6 with low binding energy . The docking score of COVID-19 spike protein was stronger than the docking score of spike protein with ACE2.The surface view of complex reveals that the binding pocket of STRA6- Spike protein and Spike ACE 2 complexes with RMSD (189.44 Å , 1.00 Å ) representatively and docking score (-341.21 ,-354.68) kcal/mol the quality of the receptor and the ligand are LGscore and MaxSub ( 2.416 , 0.147 ). The spike to bind to RDB of the STRA 6 protein in the ILE 131C , MET 145C , HIS 86A with interface residue( 4.961 , 4.953 and 3.271) representatively.In conclusionSTRA6 mutations results in a broad spectrum of complication related to malformations including congenital heart defects , anophthalmia, alveolar capillary dysplasia, diaphragmatic hernia, lung hypoplasia and mental retardation. Moreover, Retinoic acid metabolism is defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS. Therefore, we believe that this novel discovery that STRA6 receptor acts as a novel binding receptor for COVID-19 will shed new light on effective treatments against COVID-19 and may explain many pre and post-covid-91 symptoms with unknown etiology . Therefore, reconstitution of the signaling of retinoid may prove to be a valid strategy for COVID-19 management. According to our findings Vitamin A supplements and retinoic acid will be promising and effective treatments for COVID-19 infection and its unknown aetiology symptoms. it worth mentioning that aerosolized all- trans retinoic acid is currently under clinical investigation (ClinicalTrials.gov Identifier: NCT05002530)

Post-COVID-19 Anosmia and Therapies: Stay Tuned for New Drugs to Sniff Out

“…Regarding the use of aerosolized retinoic acid, the authors suggested that STRA6 function was lost due to a blockade by the COVID-19 spike protein, which binds to it with high affinity, hijacking the signaling pathway, leading to disruption of retinoic acid synthesis and vitamin A deficiency. This is because Elkazzaz et al indicated that the administrated retinoic acid would facilitate cellular uptake of retinol in immune cells through the impaired transport function of the STRA6 receptor by binding to the RBD of the SARS-CoV-2 spike protein, leading to an improvement in immune system homeostasis [ 48 , 69 ]. This may also be applicable to olfactory epithelial homeostasis because retinoic acid insufficiency in the olfactory epithelium causes cell failure in progenitor cells and, consequently, olfactory neuron differentiation is not maintained.…”

13 cis retinoic acid improved the outcomes of COVID-19 patients. A randomized clinical trial

“…The development of effective treatment options against COVID-19 will only be possible with a clear understanding of the pathogenesis of COVID-19. Retinoic acid metabolism is defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS (10). Therefore, reconstitution of the signaling of retinoid may prove to be a valid strategy for COVID-19 management.…”

“…This article investigates the potential effect of 13 cis retinoic acid, a potential metabolite of Vitamin A in the treatment of SARS-CoV-2 owing to its ability to downregulate angiotensin Converting Enzyme (ACE2) receptor and angiotensin II expression and its impact on immunity, androgen receptors, inflammatory IL-6, thrombin and respiratory diseases. Moreover, our recent molecular docking based analysis showed that spike protein Receptor Binding Domain (RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor(10). STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid 6 (STRA6), which 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 (10).…”

“…Moreover, our recent molecular docking based analysis showed that spike protein Receptor Binding Domain (RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor(10). STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid 6 (STRA6), which 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 (10). The primary ligand of STRA6 (vitamin A/retinol) was shown to be drastically reduced during COVID-19 infection, which support the role of retinoic acid in COVID-19 treatment (10).…”