Analysis of Interaction between odorant receptors and flexible spike of SARS CoV-2- key to loss of smell.

The vaccine development for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is primarily focused on structure of the spike (S) protein. The heavy glycosylation of S with flexible hinges at stalk shields from antibodies. The flexible nature of hinges may be one of the important factors which are responsible for binding the odorant receptor of those neurons which are responsible for the loss of smell in patients with COVID-19 infection. In this study strong and stable bond formation results from reaction between R:14: Trp and Phe at the residue, the expected outcome of this research may help in designing a novel vaccine that targets the flexible hinges of SARS-CoV-2. The difference in the conformational structure of S protein and their binding with the odorant receptor in COVID-19 are prime factor for the loss of smell and taste in patients supported by the concept of Antigen (epitope) Antibody interaction by stable formation of Hydrogen bond among odorant receptor and the S protein. The flexibility of structural proteins determines if the antibodies or other defense proteins produced are homologous participating in antigen antibody reaction thus maintaining the most neutralization sensitive epitope to produce the new vaccine strain or in isolating most effectively neutralizing human mABs. Molecular and atomic level details potentiate the design and screening of small molecules that can inhibit the fusion at entry level or at odorant receptors and potentially be used in prevention and treatment of infection particularly when formulated as nasal drops, paving a new approach for pharmacologist in treatment of COVID-19 infection.

Gut Microbiota Disruption in COVID-19 or Post-COVID Illness Association with severity biomarkers: A Possible Role of Pre / Pro-biotics in manipulating microflora.

Coronavirus disease (COVID-19), a coronavirus-induced illness attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, is thought to have first emerged on November 17, 2019. According to World Health Organization (WHO). COVID-19 has been linked to 379,223,560 documented occurrences and 5,693,245 fatalities globally as of 1st Feb 2022. Influenza A virus that has also been discovered diarrhea and gastrointestinal discomfort was found in the infected person, highlighting the need of monitoring them for gastro intestinal tract (GIT) symptoms regardless of whether the sickness is respiration related. The majority of the microbiome in the intestines is Firmicutes and Bacteroidetes, while Bacteroidetes, Proteobacteria, and Firmicutes are found in the lungs. Although most people overcome SARS-CoV-2 infections, many people continue to have symptoms months after the original sickness, called Long-COVID or Post COVID. The term "post-COVID-19 symptoms" refers to those that occur with or after COVID-19 and last for more than 12 weeks (long-COVID-19). The possible understanding of biological components such as inflammatory, immunological, metabolic activity biomarkers in peripheral blood is needed to evaluate the study. Therefore, this article aims to review the informative data that supports the idea underlying the disruption mechanisms of the microbiome of the gastrointestinal tract in the acute COVID-19 or post-COVID-mediated elevation of severity biomarkers.

A European pharmacotherapeutic agent roflumilast exploring integrated preclinical and clinical evidence for SARS CoV-2 mediated inflammation to organ damage.

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma) seem more susceptible to severe illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Under preclinical studies, roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline and right heart thickening. The current study reviewed existing data that the PDE-4 inhibitor, a roflumilast, protects renal tissues and other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related to a decrease in oxidative and inflammatory burden, caspase-3 suppression and increased protein kinase A (PKA)/cyclic A.M.P. (cAMP) levels in renal and other organ tissue.

Disruption of the biological activity of protease-activated receptors2/4 in adults rather than children in SARS CoV-2 virus-mediated mortality in COVID-19 infection.

One of the most remarkable results in 2019 is the reduced prevalence and death of children from coronavirus infection (COVID-19). In 2019, a worldwide pandemic impacted around 0.1 billion individuals, with over 3.5 million mortality reported in the literature. There is minimal knowledge on SARS-CoV-2 infection immunological responses in kids. Studies have been focused mostly on adults and children since the course of pediatric sickness is often short. In adults, severe COVID-19 is related to an excessive inflammatory reaction. Macrophages and monocytes are well known to contribute to this systemic response, although numerous lines are indicative of the importance of neutrophils. An increased number of neutrophils and neutrophil to lymphocyte ratios are early signs of SARS-CoV-2 and a worse prognosis. In this study that it is crucial to monitor PAR2 and PAR4 expression and function (since nursing children have elevated levels) and the inhibiting the normal physiology through the use of anticoagulants may exacerbate the problem in adults. Thus, in COVID-19 infection, we propose the use of antiplatelet (thromboxane A2 inhibitors), if required rather than anticoagulants (FXa and thrombin Inhibitors).

Antiviral effects of probiotic metabolites on COVID-19.

SARS coronavirus (COVID-19) is a real health challenge of the 21st century for scientists, health workers, politicians, and all humans that has severe cause epidemic worldwide. The virus exerts its pathogenic activity through by mechanism and gains the entry via spike proteins (S) and Angiotensin-Converting Enzyme 2 (ACE2) receptor proteins on host cells. The present work is an effort for a computational target to block the residual binding protein (RBP) on spike proteins (S), Angiotensin-Converting Enzyme 2 (ACE2) receptor proteins by probiotics namely Plantaricin BN, Plantaricin JLA-9, Plantaricin W, Plantaricin D along with RNA-dependent RNA polymerase (RdRp). Docking studies were designed in order to obtain the binding energies for Plantaricin metabolites. The binding energies for Plantaricin W were -14.64, -11.1 and -12.68 for polymerase, RBD and ACE2 respectively comparatively very high with other compounds. Plantaricin W, D, and JLA-9 were able to block the residues (THR556, ALA558) surrounding the deep grove catalytic site (VAL557) of RdRp making them more therapeutically active for COVID-19. Molecular dynamics studies further strengthen stability of the complexes of plantaricin w and SARS-CoV-2 RdRp enzyme, RBD of spike protein, and human ACE2 receptor. The present study present multi-way options either by blocking RBD on S proteins or interaction of S protein with ACE2 receptor proteins or inhibiting RdRp to counter any effect of COVID-19 by Plantaricin molecules paving a way that can be useful in the treatment of COVID-19 until some better option will be available.Communicated by Ramaswamy H. Sarma.

Calcium sensing receptor hyperactivation through viral envelop protein E of SARS CoV2: A novel target for cardio-renal damage in COVID-19 infection.

Over the recent decades, a number of new pathogens have emerged within specific and diverse populations across the globe, namely, the Nipah virus, the Ebola virus, the Zika virus, and coronaviruses (CoVs) to name a few. Recently, a new form of coronavirus was identified in the city of Wuhan, China. Interestingly, the genomic architecture of the virus did not match with any of the existing genomic sequencing data of previously sequenced CoVs. This had led scientists to confirm the emergence of a new CoV strain. Originally, named as 2019-nCoV, the strain is now called as SARS-CoV-2. High serum levels of proinflammatory mediators, namely, interleukin-12 (IL-12), IL-1ß, IL-6, interferon-gamma (IFNγ), chemoattractant protein-1, and IFN-inducible protein, have been repeatedly observed in subjects who were infected with this virus. In addition, the virus demonstrated strong coagulation activation properties, leading to further the understanding on the SARS-CoV2. To our understanding, these findings are unique to the published literature. Numerous studies have reported anomalies, namely, decline in the number of lymphocytes, platelets and albumins; and a rise in neutrophil count, aspartate transaminase, alanine aminotransaminase, lactate dehydrogenase, troponins, creatinine, complete bilirubin, D-dimers, and procalcitonin. Supplementation of calcium during the SARS CoV-2 associated hyperactive stage of calcium-sensing receptors (CaSR) may be harmful to the cardio-renal system. Thus, pharmacological inhibition of CaSR may prevent the increase in the levels of intracellular calcium, oxidative, inflammatory stress, and cardio-renal cellular apoptosis induced by high cytokines level in COVID-19 infection.

The Computational Intervention of Macrolide Antibiotics in the Treatment of COVID-19.

BACKGROUND: The spike (S) glycoprotein of SARS corona virus (SARS-CoV-2) and human Angiotensin- converting enzyme 2 (ACE2), are both considered the key factors for the initiation of virus infection. The present work is an effort for computational target to block the spike proteins (S) and ACE2 receptor proteins with Macrolide antibiotics like Azithromycin, (AZM), Clarithromycin (CLAM) and Erythromycin (ERY) along with RNA-dependent RNA polymerase (RdRp). METHODS: Three-dimensional structure of the SARS-CoV-2RdRp was built by the SWISS-MODEL server, the generated structure showed 96.35% identity to the available structure of SARS-Coronavirus NSP12 (6NUR), for model validity, we utilized the SWISS-model server quality parameters and Ramachandran plots. RESULTS: These compounds were able to block the residues (Arg553, Arg555, and Ala558) surrounding the deep grove catalytic site (Val557) of RdRp and thus plays an important role in tight blocking of enzyme active site. Reference drug Remdesivir was used to compare the docking score of antibiotics with RdRp. Docking value exhibited good binding energy (-7.7 up to -8.2 kcal/mol) with RdRp, indicating their potential as a potent RdRp inhibitor. Interaction of CLAM and ERY presented low binding energy (-6.8 and -6.6) with the ACE2 receptor. At the same time, CLAM exhibited a good binding affinity of -6.4 kcal/mol, making it an excellent tool to block the attachment of spike protein to ACE2 receptors. Macrolides not only affected the attachment to ACE2 but also blocked the spike proteins further, consequently inhibiting the internalization in the host cell. Three Alkyl bonds between Arg555, Ala558, and Met542 by CLAM and two Alkyl bonds of Arg624 and Lys621 by ERY plays an important role for RdRp inactivation, that can prevent the rise of newly budded progeny virus. These macrolides interacted with the main protease protein in the pocket responsible for the dimerization and catalytic function of this protein. The interaction occurred with residue Glu166, along with the catalytic residues (Tyr343, and His235) of Endoribonuclease (NSP15) protein. CONCLUSION: The present study gives three-way options either by blocking S proteins or ACE2 receptor proteins or inhibiting RdRp to counter any effect of COVID-19 by macrolide and could be useful in the treatment of COVID-19 till some better option available.

Targeting COVID-19 in Parkinson's Patients: Drugs Repurposed.

The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken the globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson 's disease (PD). Alteration in dopaminergic neurons and deficiency of dopamine in PD patients are the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common drugs under trial for COVID-19 are remdesivir, favipiravir, chloroquine and hydroxychloroquine, azithromycin along with adjunct drugs like amantadine with some monoclonal antibodies. Presently, clinically US FDA approved drugs in PD include Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), amantadine and antimuscarinic drugs. The drugs have established mechanisms of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. Conclusion and relevance of this review focus on the drugs that can be tried on PD patients with SAR CoV-2 infection, in particular, amantadine that has been approved by all the developed countries as a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and anti- Parkinson properties. To deal with the significant prognostic adverse effect of SARS-CoV-2 on PD, the present-day treatment options, clinical presentation and various mechanisms are the need of the hour.

SARS CoV-2 aggravates cellular metabolism mediated complications in COVID-19 infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the primary causative organism in corona virus disease-19 (COVID-19) infections, is a novel member of the human coronavirus family which was first identified in Wuhan, China, towards the end of 2019. This letter reveals new vital missing links in our current understanding of the mechanisms that lead to cell death triggered by ferroptotic stress in COVID-19 infection. It further reveal the importance of homocysteine mediated trans-sulfuration pathway in COVID-19 infection. Hence, Vitamin B6, folic acid, and Vitamin B12 should be incorporated in the treatment regimen for SARS CoV-2 infections to suppress complications, as the virus mediates altered host cell metabolism.

Impact of COVID-19 on Nephrology Patients: A Mechanistic Outlook for Pathogenesis of Acute Kidney Injury

CONTEXT: Some research has indicated that SARS-CoV-2 has had effects on the various functions of the renal system. Acute kidney injury (AKI) is a dangerous and broadly spread pathological illness. OBJECTIVE: In this review, we emphasize that AKI can be a severe complication of COVID-19 and highlight the importance of assessing, defining, and reporting the course of AKI. DESIGN: The research team performed a literature review, searching relevant literature databases. We searched four databases, PubMed, EMBASE, Web of Science and CNKI (Chinese Database), to identify studies reporting COVID-19. Articles published on or before May 10, 2020 were eligible for inclusion. We used the following search terms: "Coronavirus" or "2019-nCoV" or "COVID-19" or "AKI" or "renal failure" or "nephrology". SETTING: This study was take place at Jouf University, Sakaka, Al-Jouf, Saudi Arabia. RESULTS: The review showed that AKI patients, who were susceptible to a cytokine storm, showed clinical deterioration. This result allowed the current research team to develop a hypothesis of a set of adverse events in COVID-19 that proposes the modification of inflammatory pathways by stimulation of nAChRα7. The stimulation could occur by way of IL-6 / JAK2 / STAT3 / SOCS3 and NF-κB (p65)/IL-18, which work together to induce AKI and increase overall renal-related diagnostic markers, such as plasma creatinine and tubular cell damage. In addition, the functioning of the cholinergic anti-inflammatory pathway may be determined by nicotine. Pharmacological nicotine products are widely available, and their role in COVID-19-mediated AKI can be further evaluated. CONCLUSIONS: The research team concluded that the dysregulation of the cholinergic anti-inflammatory system could explain most of the clinical features of severe COVID-19.