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

Abstract

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.

Targeting COVID-19 (SARS-CoV-2) main protease through active phytocompounds of ayurvedic medicinal plants – Emblica officinalis (Amla), Phyllanthus niruri Linn. (Bhumi Amla) and Tinospora cordifolia (Giloy) – A molecular docking and simulation study

“…The size of the SARS-CoV-2 genome is around 30 kb, enclosed with 5′-cap and 3′-poly(A) tail and the structure is comprised of spike, envelope, membrane and nucleocapsid proteins [ 5 ]. Currently, there is no specific antiviral drug available for the treatment of COVID-19 and the infected patients are primarily treated only by supportive therapy [ 6 ]. As of date, several vaccine candidates such as Tozinameran, AZD1222, Covishield, Ad26.COV2·S, Vero Cell, InCoV, mRNA-1273, Sputnik V, Ad5-nCoV, EpiVacCorona, Covaxin are available for COVID-19 prevention and more than ten candidates of vaccines are under clinical trials.…”

Identification of Genotypic Variants and its Proteomic mutations of Brazilian SARS-CoV-2 Isolates

“…The protein folding information plays a key role in the therapeutic intervention of many viral diseases (Broglia et al 2005;Prathiviraj et al, 2021). The folding process of a protein determines the structural stability and drug binding specificity (Prisilla et al, 2016;Prathiviraj et al, 2016) thus it's most important to identify the folding rate of mutants (Murugan et al, 2019;Prathiviraj et al, 2021). The protein folding rate among all the identified mutants was calculated using the FOLD-RATE server (Gromiha et al, 2006).…”

“…A drastic number of mutation was found in PLPro and spike genes of the isolates BRA/CD1739-P4/2020 (11 base change), Bra/1236/2021 (13 base change), and Bra/1061/2021 (12 base change). Several reports have been previously published, that an increased level of mutation in surface glycoprotein may escort a significant role in viral contamination and disease transmission (Yan et al, 2020;Prathiviraj et al, 2021). Both synonymous and non-synonymous substitution mutation evenly occur in all isolates, which leads to drastic changes that may occur in their protein sequences (Chu and Wei, 2019).…”

“…And slow fold rate was identified in other classes (All-α, α+β:α/β and unknown ). Hence, the fluctuation in protein folding leads to replication and multiplication of SARS-CoV-2 in the new environmental niche (Prisilla et al, 2016;Prathiviraj et al, 2016;Prathiviraj et al, 2021).…”

“…Several SARS-CoV-2 variants were found to be associated with increased infectivity rate, pathogenesis and displayed a considerably faster transmission through droplets than the wild-type strain , Prathiviraj et al, 2021. The enhanced transmission rate of SARS-CoV-2 might be linked to the replication of these virus particles particularly in the upper respiratory tract and efficient replication was observed in the cultures of hAEC at a temperature of 33°C (V'kovski et al, 2021).…”