Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
Sci Rep. 2023 Jan 10;13(1):502. doi: 10.1038/s41598-023-27649-6.
Alterations in viral fitness cannot be inferred from only mutagenesis studies of an isolated viral protein. To-date, no systematic analysis has been performed to identify mutations that improve virus fitness and reduce drug efficacy. We present a generic strategy to evaluate which viral mutations might diminish drug efficacy and applied it to assess how SARS-CoV-2 evolution may affect the efficacy of current approved/candidate small-molecule antivirals for M, PL, and RdRp. For each drug target, we determined the drug-interacting virus residues from available structures and the selection pressure of the virus residues from the SARS-CoV-2 genomes. This enabled the identification of promising drug target regions and small-molecule antivirals that the virus can develop resistance. Our strategy of utilizing sequence and structural information from genomic sequence and protein structure databanks can rapidly assess the fitness of any emerging virus variants and can aid antiviral drug design for future pathogens.
仅通过对分离的病毒蛋白进行诱变研究，无法推断病毒适应性的改变。迄今为止，尚未进行系统分析以确定可提高病毒适应性并降低药物疗效的突变。我们提出了一种通用策略来评估哪些病毒突变可能降低药物疗效，并将其应用于评估 SARS-CoV-2 进化如何影响当前批准/候选小分子抗病毒药物对 M、PL 和 RdRp 的疗效。对于每个药物靶点，我们从现有结构中确定了与药物相互作用的病毒残基，以及从 SARS-CoV-2 基因组中确定了病毒残基的选择压力。这使得能够识别有希望的药物靶区和病毒可能产生耐药性的小分子抗病毒药物。我们利用基因组序列和蛋白质结构数据库中的序列和结构信息的策略可以快速评估任何新出现的病毒变异体的适应性，并有助于为未来的病原体设计抗病毒药物。
