Cordycepin and its Nucleoside Analogs for the Treatment of Systemic COVID-19 Infection

Coronavirus disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus isolated from Wuhan, China. It is a global health emergency, and there is no effective antiviral therapeutics available to date. Continuous structural genomic insights of SARS-CoV-2 proteins provide a warranty for the development of ra-tional-based antivirals. Nevertheless, a structure-based drug candidate with multiple therapeutic actions would be a practical choice of medication in the treatment of severe COVID-19 patients. Cordycepin from medicinal fungi (Cordyceps spp.) and its nucleoside analogs targeting viral RNA-dependent RNA polymerase and human RNase L have potent antiviral activity against various human viruses with additional immunomodulatory and anti-inflammatory effects. Anti-inflammation treatment is of pivotal importance and should be timely tailored to the individual patient along with antivirals. Our perspective on the combined antiviral and anti-inflammatory effects of cordycepin and its analogs suggests them as new therapeutics in the treatment of systemic COVID-19 infec-tion.Copyright © 2022 Bentham Science Publishers.

Studying folding kinetics of omicron to understand its hijack mechanism in human host cells (preprint)

Coronavirus disease (COVID-19) has rapidly expanded into a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genetic drift in global SARS-CoV-2 isolates and protein evolution have an impact on their ability to escape from current antiviral therapeutics. Hence, our study aimed to reveal how mutations in the folding kinetics of assembly and maturation proteins drive the hijack ability to emerge SARS-CoV-2 variants in humans. In this study, we predicted the folding rate of these proteins using multiple regression analysis and validated the prediction accuracy using machine learning algorithms. Hybrid machine learning using linear regression, random forest, and decision tree was used to evaluate the predicted folding rates compared with other machine learning models. In SARS-CoV-2 variants, the sequence-structure-function-folding rate link stabilizes or retains the mutated residues, making stable near-native protein structures. The folding rates of these protein mutants were increased in their structural classes, particularly β-sheets, which accommodated the hijacking ability of new variants in human host cells. E484A and L432R were identified as potent mutations that resulted in drastic changes in the folding pattern of the spike protein. We conclude that receptor-binding specificity, infectivity, multiplication rate, and hijacking ability are directly associated with an increase in the folding rate of their protein mutants.

A hijack mechanism of Indian SARS-CoV-2 isolates for relapsing contemporary antiviral therapeutics.

Coronavirus disease (COVID-19) rapidly expands to a global pandemic and its impact on public health varies from country to country. It is caused by a new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is imperative for relapsing current antiviral therapeutics owing to randomized genetic drift in global SARS-CoV-2 isolates. A molecular mechanism behind the emerging genomic variants is not yet understood for the prioritization of selective antivirals. The present computational study was aimed to repurpose existing antivirals for Indian SARS-CoV-2 isolates by uncovering a hijack mechanism based on structural and functional characteristics of protein variants. Forty-one protein mutations were identified in 12 Indian SARS-CoV-2 isolates by analysis of genome variations across 460 genome sequences obtained from 30 geographic sites in India. Two unique mutations such as W6152R and N5928H found in exonuclease of Surat (GBRC275b) and Gandhinagar (GBRC239) isolates. We report for the first time the impact of folding rate on stabilizing/retaining a sequence-structure-function-virulence link of emerging protein variants leading to accommodate hijack ability from current antivirals. Binding affinity analysis revealed the effect of point mutations on virus infectivity and the drug-escaping efficiency of Indian isolates. Emodin and artinemol suggested herein as repurposable antivirals for the treatment of COVID-19 patients infected with Indian isolates. Our study concludes that a protein folding rate is a key structural and evolutionary determinant to enhance the receptor-binding specificity and ensure hijack ability from the prevalent antiviral therapeutics.

Genomics insights of SARS-CoV-2 (COVID-19) into target-based drug discovery.

Coronavirus disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a global health emergency and no clinically approved vaccines or antiviral drugs available to date. Intensive research on SARS-CoV-2 is urgently warranted to understand its pathogenesis and virulence mechanisms and to discover target-based antiviral therapeutics. Among various research logics, current bioinformatics highlights novel testable hypotheses for systematic drug repositioning and designing against COVID-19. A total of 121 articles related to bioinformatics facets of this virus were collected from the PubMed Central. The content of each investigation was comprehensively reviewed, manually curated, and included herein. Interestingly, 109 COVID-19-related literature published in 2020 (January-June) were included in this review. The present article emphasizes novel resource development on its genome structure, evolution, therapeutic targets, drug designing, and drug repurposing strategies. Genome organization, the function of coding genes, origin, and evolution of SARS-CoV-2 is described in detail. Genomic insights into understanding the structure-function relationships of drug targets including spike, main protease, and RNA-dependent RNA polymerase of SARS-CoV-2 are discussed intensively. Several molecular docking and systems pharmacology approaches have been investigated some promising antiviral drugs against SARS-CoV-2 based on its genomic characteristics, pathogenesis mechanism, and host specificity. Perhaps, the present genomic insights of this virus will provide a lead to the researchers to design or repurpose of antiviral drugs soon and future directions to control the spread of COVID-19.