Padhi Aditya K, Shukla Rohit, Saudagar Prakash, Tripathi Timir
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173234, India.
iScience. 2020 Dec 26;24(1):101992. doi: 10.1016/j.isci.2020.101992. eCollection 2021 Jan 22.
The use of remdesivir to treat COVID-19 will likely continue before clinical trials are completed. Due to the lengthening pandemic and evolving nature of the virus, predicting potential residues prone to mutation is crucial for the management of remdesivir resistance. Using a rational ligand-based interface design complemented with mutational mapping, we generated a total of 100,000 mutations and provided insight into the functional outcomes of mutations in the remdesivir-binding site in nsp12 subunit of RdRp. After designing 46 residues in the remdesivir-binding site of nsp12, the designs retained 97%-98% sequence identity, suggesting that very few mutations in nsp12 are required for SARS-CoV-2 to attain remdesivir resistance. Several mutants displayed decreased binding affinity to remdesivir, suggesting drug resistance. These hotspot residues had a higher probability of undergoing selective mutation and thus conferring remdesivir resistance. Identifying the potential residues prone to mutation improves our understanding of SARS-CoV-2 drug resistance and COVID-19 pathogenesis.
在临床试验完成之前，瑞德西韦用于治疗新冠病毒疾病（COVID-19）的情况可能会持续。由于疫情的延长以及病毒不断演变的特性，预测易于发生突变的潜在残基对于管理瑞德西韦耐药性至关重要。我们采用基于配体的合理界面设计并辅以突变图谱分析，总共生成了100,000个突变，并深入了解了RNA依赖性RNA聚合酶（RdRp）的nsp12亚基中瑞德西韦结合位点突变的功能结果。在设计了nsp12的瑞德西韦结合位点中的46个残基后，这些设计保留了97%-98%的序列同一性，这表明严重急性呼吸综合征冠状病毒2（SARS-CoV-2）获得瑞德西韦耐药性所需的nsp12突变非常少。几个突变体对瑞德西韦的结合亲和力降低，表明出现了耐药性。这些热点残基发生选择性突变并因此产生瑞德西韦耐药性的可能性更高。识别易于发生突变的潜在残基有助于我们更好地理解SARS-CoV-2耐药性和COVID-19发病机制。
