Coronil, a Tri-Herbal Formulation, Attenuates Spike-Protein-Mediated SARS-CoV-2 Viral Entry into Human Alveolar Epithelial Cells and Pro-Inflammatory Cytokines Production by Inhibiting Spike Protein-ACE-2 Interaction.

PURPOSE: Coronil is a tri-herbal formulation containing extracts from Withania somnifera, Tinospora cordifolia, and Ocimum sanctum. Recently, it was shown that Coronil rescued humanized zebrafish from SARS-CoV-2 induced pathologies. Based on reported computational studies on the phytochemicals present in Coronil, it could be a potential inhibitor of SARS-CoV-2 entry into the host cell and associated cytokines' production. METHODS: Through an ELISA-based biochemical assay, effects of Coronil on interaction between ACE-2 and different mutants of viral spike (S) protein, crucial for viral invasion of host cell, were evaluated. Additionally, using recombinant pseudoviruses having SARS-CoV-2 spike (S) protein in their envelopes and firefly luciferase reporter in their genomes, effects of Coronil on virus entry into human alveolar epithelial cells were evaluated through luciferase assay. UHPLC profiled Coronil also modulated S-protein mediated production of pro-inflammatory cytokines in A549 cells, like interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α), as evaluated through RT-qPCR and ELISA. RESULTS: Coronil effectively inhibited the interaction of ACE-2 not only with the wild-type S protein (SWT) but also with its currently prevalent and more infectious variant (SD614G) and another mutant (SW436R) with significantly higher affinity toward ACE-2. Treatment with Coronil significantly reduced the increased levels of IL-6, IL-1ß, and TNF-α in A549 cells incubated with different S-protein variants in a dose-dependent manner. Likewise, it also prevented the SARS-CoV-2 S-protein pseudotyped vesicular stomatitis virus (VSVppSARS-2S) mediated cytokine response in these cells by reducing entry of pseudoviruses into host cells. CONCLUSION: Coronil prevented SARS-CoV-2 S-protein mediated viral entry into A549 cells by inhibiting spike protein-ACE-2 interactions. SARS-CoV-2 S protein induced inflammatory cytokine response in these cells was also moderated by Coronil.

Repurposing therapeutics for COVID-19: Rapid prediction of commercially available drugs through machine learning and docking.

BACKGROUND: The outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS-CoV-2. METHODS AND FINDINGS: We perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we found that 3 of the drugs fulfils the criterions well among which the antiretroviral drug Amprenavir (DrugBank ID-DB00701) would probably be the most effective drug based on the selected criterions. CONCLUSIONS: Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID-19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.

An Assessment on Impact of COVID-19 Infection in a Gender Specific Manner.

Coronavirus disease 2019 (COVID-19) is caused by novel coronavirus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first time reported in December 2019 in Wuhan, China and thereafter quickly spread across the globe. Till September 19, 2020, COVID-19 has spread to 216 countries and territories. Severe infection of SARS-CoV-2 cause extreme increase in inflammatory chemokines and cytokines that may lead to multi-organ damage and respiratory failure. Currently, no specific treatment and authorized vaccines are available for its treatment. Renin angiotensin system holds a promising role in human physiological system specifically in regulation of blood pressure and electrolyte and fluid balance. SARS-CoV-2 interacts with Renin angiotensin system by utilizing angiotensin-converting enzyme 2 (ACE2) as a receptor for its cellular entry. This interaction hampers the protective action of ACE2 in the cells and causes injuries to organs due to persistent angiotensin II (Ang-II) level. Patients with certain comorbidities like hypertension, diabetes, and cardiovascular disease are under the high risk of COVID-19 infection and mortality. Moreover, evidence obtained from several reports also suggests higher susceptibility of male patients for COVID-19 mortality and other acute viral infections compared to females. Analysis of severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS) epidemiological data also indicate a gender-based preference in disease consequences. The current review addresses the possible mechanisms responsible for higher COVID-19 mortality among male patients. The major underlying aspects that was looked into includes smoking, genetic factors, and the impact of reproductive hormones on immune systems and inflammatory responses. Detailed investigations of this gender disparity could provide insight into the development of patient tailored therapeutic approach which would be helpful in improving the poor outcomes of COVID-19. Graphical abstract.

Natural molecules having anti-SARS- CoV activity - cannot they be effective against SARS-CoV-2?

In the current scenario, developing treatments, identifying cures and formulating intervention strategies to fight against the COVID-19 outbreak, have become the major concern for researchers globally. Several studies have confirmed the molecular pathway of COVID-19 virulence that involves activation of proteins like angiotensin-converting enzyme 2 (ACE2), angiotensin (AT) receptor which is mainly AT1, and transmembrane protease serine 2 (TMPRSS2). Since the virus needs the involvement of these proteins, over and above its spike protein, for activation and infecting the host, it is obvious that targeting or blocking the activation of these molecules may play a critical role in the development of therapeutics for the cure and management of COVID-19. Many studies have been reported and several are ongoing to find a cure using these molecules as a target. While initially COVID-19 was thought to be affecting the human respiratory system, recent shreds of evidence indicate that this infection can reach beyond the lungs. It can invade and rampage almost all the organs in the body, and 'cytokine storm' is considered to be responsible for this. The reason for disease severity is not what matters anymore now, everyone is hoping for a cure soon enough. Therefore, there is an urgent need to search for some novel drugs/chemicals. Towards this end, natural products can contribute immensely since they have a long history of usage for the cure and management of various ailments, including viral infections. Various natural products (mainly from plants) have structural similarities to the molecules which by AT has been shown to interact with targets used by COVID-19 during its infection. This is indeed a positive indication for the development of natural products-based therapeutics. This aspect, therefore, warrants serious consideration for the cure and management of the COVID-19 pandemic.

Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and Hypertension.

Severe acute respiratory syndrome corona virus - 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in host's cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.