Major Insights in Dynamics of Host Response to SARS-CoV-2:Impacts and Challenges

The coronavirus disease 2019 (COVID-19), a pandemic declared by the World Health Organization on March 11, 2020, is caused by the infection of highly transmissible species of a novel coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of July 25, 2021, there are 194,372,584 cases and 4,167,937 deaths with high variability in clinical manifestations, disease burden, and post-disease complications among different people around the globe. Overall, COVID-19 is manifested as mild to moderate in almost 90% of the cases and only the rest 10% of the cases need hospitalization. However, patients with older age and those having different comorbidities have made worst the pandemic scenario. The variability of pathological consequences and clinical manifestations of COVID-19 is associated with differential host–SARS-CoV-2 interactions, which are influenced by the factors that originated from the SARS-CoV-2 and the host. These factors usually include the genomic attributes and virulent factors of the SARS-CoV-2, the burden of coinfection with other viruses and bacteria, age and gender of the individuals, different comorbidities, immune suppressions/deficiency, genotypes of major histocompatibility complex, and blood group antigens and antibodies. We herein retrieved and reviewed literatures from PubMed, Scopus, and Google relevant to clinical complications and pathogenesis of COVID-19 among people of different age, sex, and geographical locations; genomic characteristics of SARS-CoV-2 including its variants, host response under different variables, and comorbidities to summarize the dynamics of the host response to SARS-CoV-2 infection; and host response toward approved vaccines and treatment strategies against COVID-19. After reviewing a large number of published articles covering different aspects of host response to SARS-CoV-2, it is clear that one aspect from one region is not working with the scenario same to others, as studies have been done separately with a very small number of cases from a particular area/region of a country. Importantly, to combat such a pandemic as COVID-19, a conclusive understanding of the disease dynamics is required. This review emphasizes on the identification of the factors influencing the dynamics of host responses to SARS-CoV-2 and offers a future perspective to explore the molecular insights of COVID-19

Beta, Delta, and Omicron, Deadliest Among SARS-CoV-2 Variants: A Computational Repurposing Approach

SARS-CoV-2 has been highly susceptible to mutations since its emergence in Wuhan, China, and its subsequent propagation due to containing an RNA as its genome. The emergence of variants with improved transmissibility still poses a grave threat to global health. The spike protein mutation is mainly responsible for higher transmissibility and risk severity. This study retrieved SARS-CoV-2 variants structural and nonstructural proteins (NSPs) sequences from several geographic locations, including Africa, Asia, Europe, Oceania, and North and South America. First, multiple sequence alignments with BioEdit and protein homology modeling were performed using the SWISS Model. Then the structure visualization and structural analysis were performed by superimposing against the Wuhan sequence by Pymol to retrieve the RMSD values. Sequence alignment revealed familiar, uncommon regional among variants and, interestingly, a few unique mutations in Beta, Delta, and Omicron. Structural analysis of such unique mutations revealed that they caused structural deviations in Beta, Delta, and Omicron spike proteins. In addition, these variants were more severe in terms of hospitalization, sickness, and higher mortality, which have a substantial relationship with the structural deviations because of those unique mutations. Such evidence provides insight into the SARS-CoV-2 spike protein vulnerability toward mutation and their structural and functional deviations, particularly in Beta, Delta, and Omicron, which might be the cause of their broader coverage. This knowledge can help us with regional vaccine strain selection, virus pathogenicity testing, diagnosis, and treatment with more specific vaccines

Main protease inhibitors and drug surface hotspots for the treatment of COVID-19: A drug repurposing and molecular docking approach

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (−10.9 kcal/mol) and its analog (CID 131982844) (−16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial

Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absenceof a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen outthe effective drug candidates from the approved main protease protein (MPP) inhibitors and theirderivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking wereemployed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors againstHIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamidewere studied as control. The target drug surface hotspot was also investigated through the moleculardocking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likenessof the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and itsanalog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitorcompared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study amongthe screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspotin the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its\u27 analog (CID 131982844),may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on themain protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevirand its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approvedMPP inhibitors. </div