Changde Research Centre for Artificial Intelligence and Biomedicine, College of Life and Environmental Sciences, Hunan University of Arts and Science, Changde, Hunan 415000, China.
National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, United States.
Biochem Pharmacol. 2021 Jul;189:114424. doi: 10.1016/j.bcp.2021.114424. Epub 2021 Jan 19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Three viral proteins, the spike protein (S) for attachment of virus to host cells, 3-chymotrypsin-like cysteine protease (M) for digestion of viral polyproteins to functional proteins, and RNA-dependent-RNA-polymerase (RdRp) for RNA synthesis are the most critical proteins for virus infection and replication, rendering them the most important drug targets for both antibody and chemical drugs. Due to its low-fidelity polymerase, the virus is subject to frequent mutations. To date, the sequence data from tens of thousands of virus isolates have revealed hundreds of mutations. Although most mutations have a minimum consequence, a small number of non-synonymous mutations may alter the virulence and antigenicity of the mutants. To evaluate the effects of viral mutations on drug safety and efficacy, we reviewed the biochemical features of the three main proteins and their potentials as drug targets, and analyzed the mutation profiles and their impacts on RNA therapeutics. We believe that monitoring and predicting mutation-introduced protein conformational changes in the three key viral proteins and evaluating their binding affinities and enzymatic activities with the U.S. Food and Drug Administration (FDA) regulated drugs by using computational modeling and machine learning processes can provide valuable information for the consideration of drug efficacy and drug safety for drug developers and drug reviewers. Finally, we propose an interactive database for drug developers and reviewers to use in evaluating the safety and efficacy of U.S. FDA regulated drugs with regard to viral mutations.
严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引发了全球大流行。病毒的三种蛋白，即用于病毒附着宿主细胞的刺突蛋白（S）、用于消化病毒多蛋白为功能蛋白的 3-糜蛋白酶样半胱氨酸蛋白酶（M）和用于 RNA 合成的 RNA 依赖性 RNA 聚合酶（RdRp），是感染和复制病毒的最关键蛋白，使它们成为抗体和化学药物的最重要药物靶点。由于其低保真度聚合酶，病毒经常发生突变。迄今为止，从数万种病毒分离株获得的序列数据揭示了数百种突变。虽然大多数突变的影响最小，但少数非同义突变可能改变突变体的毒力和抗原性。为了评估病毒突变对药物安全性和疗效的影响，我们综述了这三种主要蛋白的生化特征及其作为药物靶点的潜力，并分析了突变谱及其对 RNA 治疗的影响。我们相信，通过计算建模和机器学习过程监测和预测三种关键病毒蛋白中突变引入的蛋白构象变化，并评估它们与美国食品和药物管理局（FDA）监管药物的结合亲和力和酶活性，可以为药物开发者和药物审查者提供有价值的信息，以考虑药物疗效和药物安全性。最后，我们提出了一个交互式数据库，供药物开发者和审查者用于评估美国 FDA 监管药物的安全性和疗效，以应对病毒突变。
