BackgroundThe COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Although, ACE2 has been identified as the principal host cell receptor of 2019-nCoV, and it is thought to play a critical role in the virus's entrance into the cell and subsequent infection, many cells can be infected by COVID-19 while also expressing little or no ACE2. Unlike other viral infections, COVID-19 is characterized by widespread and severe systemic manifestations, immune dysregulation and multi-organ involvement. In addition, the range of serious inflammatory, neuropsychiatric and autoimmune diseases called post-COVID syndromes are now left behind as disease tables. This wide and diverse spectrum of diseases seen in COVID-19 cannot be explained by the mechanism of viral tropism mediated by ACE2 and TMPRSS2 receptors. It is possible that different receptor and signaling mechanisms that cannot be explained by the viral tropism mechanism play a role in the pathogenesis of acute systemic effects and chronic post-COVID syndromes in COVID-19. It was showed that COVID-19 infection leads to a loss of smell (anosmia) but the COVID-19 entry receptors, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. Moreover It was demonstrated that COVID-19 could infect lymphocyte through its ACE2 receptors, but numerous studies found that lymphocytes don't express ACE2 receptors or express it with a little, insufficient amount. It is clear from the information and findings presented and addressed in our article that COVID-19 not only binds to ACE2, but also to additional receptors, leading to more disease lethality and existence of covid-19 symptoms which remain unexplained. As a result, discovering and identifying these receptors could lead to the development of new treatments that could suppress COVID-19 and reduce its severity and pathogenicity. Herein, we insilico discovered that blocking of STRA6 by the SARS-CoV-2 spike protein could disrupt the retinoid signaling mechanism and leads to pathogenetic consequences through some other inflammatory pathways.MethodsThe 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)ResultsOur results showed that COVID-19 Spike protein exhibited a high binding affinity for human STRA6 and a low binding energy with it. 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. 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. The docking of STRA6 target protein with spike viral protein revealed the involvement of the spike protein into the extracellular and membrane part of the STRA6 receptor and amino acids residues of STRA6 along with spike protein which make interactions and play an important role in formation of complexes. The corresponding distances about the residue contacts between proteins STRA6- Spike protein complex are documented here where the STRA6- Spike protein complexes binding site are the RDB of the CHOLESTEROL in STRA6 receptor which bind with interface residue( ARG 511A , VAL 512A THR 515A ALA 516A ASN 519A with interface residue degree (2.965 , 3.595 , 3.286 , 4.592 , and 4.235) representatively, also the ability of 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. STRA6- Spike protein complex with PDB ID (5SY1 , 6LZG).ConclusionsSTRA6 is a critical regulator of many biological processes thorough initiating cellular retinol uptake, in different organs and tissues as in immune cells for improving the immune system homeostasis in various populations. Our docking study reveals that COVID-19 spike protein binds directly to the integral membrane receptor (STRA6) in addition to its binding sites of the cholesterol. STRA6 mediates cellular uptake of retinol (vitamin A) by recognizing a molecule of RBP-retinol to trigger release and internalization of retinol . Therefore COVID-19 may leads to downregulation of STRA6 receptor leading to inhibition the regulatory function of retinoic acid and cholesterol helping in existing symptoms and complications including lymhopenia, Nuerogical disorders, Ineffective RIG-I pathway, Interferon inhibition, Cytokine storm, Diabetes, Hormonal imbalance, Thrombosis, and Smell loss. Therefore, we believe that this novel discovery that STRA6 receptor acts as a novel binding receptor for COVID-19 could explain COVID-19 severity and its common symptoms with unknown aetiology . Moreover, retinoic acid metabolism was found to be defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS .As a result reconstitution of the retinoid signaling may prove to be a valid strategy for COVID-19 management. We suggest that Vitamin A metabolites ,especially, 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 and 13 cis retinoic acid is currently under clinical investigation (ClinicalTrials.gov Identifier: NCT05002530, NCT04353180)

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Given the urgency of the COVID-19 pandemic, the clinical investigation of approved drugs is a promising alternative to find a timely effective treatment. In this randomized trial, we investigated the activity of both oral and aerosolized 13 cis retinoic acid in the treatment of SARS-COV-2 added to standard of care treatment in patients with COVID-19 versus standard of care treatment alone. This was a randomized controlled trial conducted at Kafrelsheikh Universitys Quarantine Hospitals, Egypt. After obtaining informed consent, forty patients with a confirmed diagnosis of COVID-19 were enrolled in the study. They were randomly assigned to one of two groups: Group I; 20 patients received aerosolized and oral 13 cis retinoic acid plus standard of care treatment (13 cis RA group) and Group II; 20 patients received only standard care treatment as a control group. The two groups were age and gender matched. There was no statistically significant difference between them in any of the baseline characteristics or laboratory parameters. The results showed that there was a high significant difference between the two groups regarding intensive care unit (ICU) admission, mortality and improvement (P<0.05). Only 10.52 % of patients in the 13 cis retinoic acid group needed ICU admission compared to 28.57 % in the control arm. There was no mortality in the 13 cis retinoic acid group, whereas about 14.35% were died in the group II. All patients who received 13 cis retinoic acid noticed a high improvement (P<0.001), and the mean value for clinical improvement was 16 days. There was no significant difference regarding the laboratory parameters before and after 14 days of treatment in the group of patients received the standard of care treatment (P=0.66). Univariate logistic regression analysis showed overall mortality was significantly related to the patients age, serum ferritin, C-reactive protein, oxygen saturation, the presence of diabetes mellitus, obesity, and abdominal pain. We conclude that 13 cis retinoic acid is a promising drug in the treatment of patients with COVID-19 infection, when added to the standard of care treatment.

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)

Interleukin 6 (IL-6) is a type of interleukin that functions as both a pro-inflammatory and anti-inflammatory cytokine. It is encoded by the IL6 gene in humans. Both COVID-19 infection and S-Protein Based Vaccines for COVID-19 were found to induce the production of proinflammatory IL-6, and also, strenuous exercise was found to induce IL-6 secretion by the skeletal muscles via lactate. Exercise causes skeletal muscle cells to release IL-6, and it raises the plasma concentration of IL-6 100 times higher than at rest . Exercise-induced IL-6 release is highly correlated with exercise intensity and duration; thus, IL-6 is regarded as an energy sensor released by contracting muscles. but It was found that rare adverse effects such as myocardial infarction and coagulation abnormalities , are rarely associated with S-Protein Based Vaccines for COVID-19. Recently, it was showed in a study that most patients who experienced myocarditis after COVID-19 vaccine were young male youth aged 16 to 29 years had the highest incidence of myocarditis. Interestingly, It was observed that IL-6 was linked to adverse effects such as thrombosis and myocarditis, both of which are similar to that was caused by COVID-19 infection, and that S-Protein Based Vaccines for COVID-19. Here, we propose a testable hypothesis that strenuous exercise could be a risk and cofactor helping in the existing of these adverse effects in young people such as myocarditis and thrombosis via induction the secretion of proinflammatory IL-6. In our prospective observational study we will assess the possible correlation among the strenuous exercise , IL-6, myocarditis and thrombosis. The study will be multi-center and will involve young patient who will be vaccinated with first ,second and third dose of S-Protein Based Vaccines for COVID-19 (Moderna and Pfizer-BioNTech vaccine). Pfizer and BioNTech have successfully developed the BNT162b2 mRNA vaccine, which consists of the full-length S glycoprotein with the K986P and V987P mutation sites. Also, Moderna's mRNA-1273 vaccine contains the coding sequence for a S glycoprotein stabilized by a pair of proline substitutions (K986P/V987P), a transmembrane anchor, and an intact S1-S2 cleavage site

Despite the intense research work since the beginning of the pandemic, the pathogenesis of COVID-19 is not yet clearly understood. The previous mechanism of COVID-19, based on ACE2 tropism and explained through a single receptor, is insufficient to explain the pathogenesis due to the absence of angiotensin-converting enzyme 2 (ACE2) receptors in most of the affected organs. In the current study, we used the PatchDock server to run a molecular docking study of both the gonadotropin-releasing hormone receptor (GnRHR) and G-protein-coupled-receptor (GPCR) with the SARS-CoV-2 spike protein. Molecular Dynamics (MD) simulations were run to analyze the stability of the complexes using the GROMACS package. The docking results showed a high affinity between the spike protein with the GnRHR (−1424.9 kcal/mol) and GPCR (−1451.8 kcal/mol). The results of the MD simulations revealed the significant stability of the spike protein with the GnRHR and GPCR up to 100 ns. The SARS-CoV-2 spike protein had strong binding interactions with the GPCRs and GnRHRs, which are highly expressed in the brain, endocrine organs, and olfactory neurons. This study paves the way towards understanding the complex mechanism of neuroendocrine involvement and peripheral organ involvement, may explain the changing symptoms in patients due to new variants, and may lead to the discovery of new drug targets for COVID-19. In vitro studies involving genetic engineering or gene knockdown of the GPCRs and GnRHRs are needed to further investigate the role of these receptors in COVID-19 pathogenesis.

Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory immunological illnesses; it can also occur with COVID-19 infection . CSS is characterized by a disruption in cytokine synthesis, including regulatory , pro-inflammatory andanti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17and Th1mediated) response. In the pathophysiology of CSS, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19pathogenesis was established in a wide variety of researches , which reported that the plasma concentration of IL-6was raised in COVID-19 patients with severe symptoms .COVID-19 spike protein binding to angiotensin-converting enzyme 2 (ACE2), the virus's cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation which may lead to cytokine storm . Therefore, the development of new naturaltherapies and repurposing some drugs such as Phenformin and Docosahexaenoic acidthat could compete with COVID-19 for ACE2 binding or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals anddrugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibitthe hyper activation of IL-6. Our results revealed that a five phytochemicalsincluding Epigallocatechin gallate (EGCG) , bromelain, luteolin , vitexin and isovitexin)showed a high binding affinities with best interactions with the active sites of IL-6 .The binding affinities of these phytochemicalsincluding,EGCG , bromelain, luteolin , vitexin and isovitexinwith IL-6 were (-7.7,-6.7, -7.4, -7.2 and -7.3 ), respectively. In addition to ,phenforminshowed a high binding affinity with best interactions with the active sites of IL-6 and ACE2 . The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2).Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA)with IL-6 was (-5.3) and with AC2 (-6.3).

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 shown to be the main entry receptor of COVID-19, but here, in our docking analysis , we predicted and discovered a novel receptor called STRA6 that may play a critical role in the pathogenicity of COVID-19 and explain the common pre and post COVID-19 symptoms with uncertain 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. In agreement to our findings, the main ligand of STRA6 (vitamin/retinol) was found to be significantly reduced during COVID-19 infection.

A common symptoms of COVID-19 is a change or disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems including Hypogonadism and Hypothyrodism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their etiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause hormonal imbalance ,headache, eye-ache, earache, dizziness and hallucination. It was showed that G-protein coupled receptors (GPCR) and Gonadotropin-releasing hormone receptors (GnRHR), a subtype of GPCR were expressed sufficiently in olfactory region and hypothalamus as well as the lung Herein by using molecular docking and stimulation analysis, we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCR). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCR in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure. Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHR) as a novel binding receptor of COVID-19. In the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnHR and GPCR receptor protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHR and GPCR proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of inhibitor molecule in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field .This analysis of simulations of molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GPCR and GnRHR. Results indicated that the spike binds to GNHR with binding energy (-1424.7 k.cal/mol) and to GPCR with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCR with the highest docking score of -1451.8 when compared to the other GNRHR complexes, which have the lowest binding affinity, as evidenced by the docking score of -1424.9.. These results signifies better conjugation of GNRHR to the binding pocket of the spike receptor in the RDB of the spike protein. Comparing the binding free energy of GPCR to GNRHR showed that the GNRHR protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRs protein were found to bind to RDB in other place in chain B of the spike. CONCLUSIONS The COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19, but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCR and GnRHR which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCR and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.