Nsp7 and Spike Glycoprotein of SARS-CoV-2 Are Envisaged as Potential Targets of Vitamin D and Ivermectin

Abstract

COVID-19 has emerged as deadly pandemic worldwide with no vaccine or suitable antiviral drugs to prevent or cure the disease. Because of the time-consuming process to develop new vaccines or antiviral agents, there has been a growing interest in repurposing some existing drugs to combat SARS-CoV-2. Vitamin D is known to be protective against acute respiratory distress syndrome (ARDS), pneumonia and cytokine storm. Recently it has been used as a repurposed drug for the treatment of H5N1 virus-induced lung injury. Circumstantial evidences indicate that people with low level of vitamin D are more susceptible to SARS-CoV-2. Although, vitamin D was suggested to interfere with viral replication, its interaction with any SARS-CoV-2 protein is unexplored yet. Beside this, ivermectin, a well-known anti-parasitic agent, exhibits potent anti-viral activities in vitro against viruses such as HIV-1 and dengue. Very recently, ivermectin has been found to reduce viral load of SARS-CoV-2 in vitro. We have analyzed available structures of SARS-CoV-2 proteins to identify probable binding partner(s) of vitamin D and ivermectin through knowledge-based docking studies and figured out possible implication of their binding in SARS-CoV-2 infection. Our observations suggest that the non-structural protein nsp7 possesses a potential site to house 25-hydroxyvitamin D3 (VDY) or the active form of Vitamin D, calcitrol. Binding of vitamin D with nsp7 likely to hamper the formation of nsp7-nsp8 complex which is required to bind with RNA dependent RNA polymerase (RdRP), nsp12 for optimal function. On the other hand, potential binding site of ivermectin has been identified in the S2 subunit of trimeric spike(S) glycoprotein of SARS-CoV-2. We propose that deeply inserted mode of ivermectin binding at three inter-subunit junctions may restrict large scale conformational changes of S2 helices which is necessary for efficient fusion of viral and host membrane. Our study, therefore, opens up avenues for further investigations to consider vitamin D and ivermectin as potential drugs against SARS-CoV-2.

A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody

“…The strongest or close to strongest binding affinity in each study was obtained for ivermectin (IVM), a macrocyclic lactone with multifaceted antiparasitic and antimicrobial activity, distributed in 3.7 billion doses for human diseases worldwide since 1987 [ 197 , 198 , 199 ]. Additional molecular modeling studies of binding to SARS-CoV-2 spike protein sites that focused on IVM in particular, including Lehrer and Rheinstein (2020) [ 200 ], likewise found strong binding affinities for IVM [ 201 , 202 , 203 , 204 , 205 ].…”

A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency

“…Although a few recommended only sunshine or 400 IU/day, none of the authors strongly opposed vitamin D supplements during the pandemic. At the extremes, some researchers recommend large bolus doses of vitamin D, or correction of deficiency, primarily for patients who are diagnosed with COVID-19, and others recommended only the dose of vitamin D needed to maintain bone health (200-400 IU/day) (44,45,73,91,108,118,160,169,(223)(224)(225)(226)(227)(228)(229). Additional authors recommend vitamin D supplements to boost the immune systems of patients diagnosed with COVID-19 (2 p , 35, 69, 71, 74, 75, 118, 120, 125, 230-233).…”

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

“…This is the same mechanism by which viral antibodies, in particular, those generated by the Pfizer and Moderna vaccines, contain the SARS-CoV-2 virus. The high binding activity of ivermectin to the SARS-CoV-2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed pathologic mechanism in COVID-19 (Dasgupta J, 2020;Dayer, 2020;Lehrer and Rheinstein, 2020;Maurya, 2020;Scheim, 2020). Ivermectin has also been shown to bind to or interfere with multiple essential structural and non-structural proteins required by the virus in order to replicate (Lehrer and Rheinstein, 2020;Sen Gupta et al, 2020).…”