Prathiviraj R, Saranya S, Bharathi M, Chellapandi P
Industrial Systems Biology Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India.
Industrial Systems Biology Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India.
Comput Biol Med. 2021 May;132:104315. doi: 10.1016/j.compbiomed.2021.104315. Epub 2021 Mar 6.
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.
冠状病毒病（COVID-19）迅速演变为全球大流行，其对公共卫生的影响因国家而异。它由一种新型病毒严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起。由于全球SARS-CoV-2分离株中随机的基因漂移，重新启用当前的抗病毒疗法势在必行。对于选择性抗病毒药物的优先级确定，新出现的基因组变异背后的分子机制尚不清楚。本计算研究旨在通过揭示基于蛋白质变体的结构和功能特征的劫持机制，为印度的SARS-CoV-2分离株重新利用现有抗病毒药物。通过分析从印度30个地理位点获得的460个基因组序列中的基因组变异，在12个印度SARS-CoV-2分离株中鉴定出41个蛋白质突变。在苏拉特（GBRC275b）和甘地讷格尔（GBRC239）分离株的核酸外切酶中发现了两个独特的突变，如W6152R和N5928H。我们首次报道了折叠速率对新兴蛋白质变体的序列-结构-功能-毒力联系的稳定/维持的影响，这导致其能够从当前抗病毒药物中获得劫持能力。结合亲和力分析揭示了点突变对病毒感染性和印度分离株的药物逃逸效率的影响。本文提出大黄素和青蒿琥酯可作为重新利用的抗病毒药物，用于治疗感染印度分离株的COVID-19患者。我们的研究得出结论，蛋白质折叠速率是增强受体结合特异性并确保从流行的抗病毒疗法中获得劫持能力的关键结构和进化决定因素。
