Bafna Khushboo, Krug Robert M, Montelione Gaetano T
Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, New York, 12180.
Department of Molecular Biosciences, John Ring LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712 USA.
ChemRxiv. 2020 Apr 21. doi: 10.26434/chemrxiv.12153615.v1.
During the current COVID-19 pandemic more than 160,000 people have died worldwide as of mid-April 2020, and the global economy has been crippled. Effective control of the SARS-CoV2 virus that causes the COVID-19 pandemic requires both vaccines and antivirals. Antivirals are particularly crucial to treat infected people during the period of time that an effective vaccine is being developed and deployed. Because the development of specific antiviral drugs can take a considerable length of time, an important approach is to identify existing drugs already approved for use in humans which could be repurposed as COVID-19 therapeutics. Here we focus on antivirals directed against the SARS-CoV2 M protease, which is required for virus replication. A structural similarity search showed that the Hepatitis C virus (HCV) NS3/4A protease has a striking three-dimensional structural similarity to the SARS-CoV2 M protease, particularly in the arrangement of key active site residues. We used virtual docking predictions to assess the hypothesis that existing drugs already approved for human use or clinical testing that are directed at the HCV NS3/4A protease might fit well into the active-site cleft of the SARS-CoV2 protease (M). docking scores for 12 HCV protease inhibitors and 9 HIV-1 protease inhibitors were determined and compared to the docking scores for an α-ketoamide inhibitor of M, which has recently been shown to inhibit SARS-CoV2 virus replication in cell culture. We identified eight HCV protease inhibitors that bound to the M active site with higher docking scores than the α-ketoamide inhibitor, suggesting that these protease inhibitors may effectively bind to the M active site. These results provide the rationale for us to test the identified HCV protease inhibitors as inhibitors of the SARS-CoV2 protease, and as inhibitors of SARS-CoV2 virus replication. Subsequently these repurposed drugs could be evaluated as COVID-19 therapeutics.
在当前的新冠疫情期间，截至2020年4月中旬，全球已有超过16万人死亡，全球经济也受到重创。有效控制导致新冠疫情的SARS-CoV2病毒既需要疫苗也需要抗病毒药物。在研发和部署有效疫苗的这段时间里，抗病毒药物对于治疗感染者尤为关键。由于开发特定的抗病毒药物可能需要相当长的时间，一种重要的方法是识别已被批准用于人类的现有药物，这些药物可以重新用作新冠治疗药物。在此，我们聚焦于针对SARS-CoV2 M蛋白酶的抗病毒药物，该蛋白酶是病毒复制所必需的。结构相似性搜索表明，丙型肝炎病毒（HCV）NS3/4A蛋白酶与SARS-CoV2 M蛋白酶具有显著的三维结构相似性，特别是在关键活性位点残基的排列上。我们使用虚拟对接预测来评估这样一个假设：已被批准用于人类使用或正在进行临床试验的、针对HCV NS3/4A蛋白酶的现有药物可能很好地契合SARS-CoV2蛋白酶（M）的活性位点裂隙。测定了12种HCV蛋白酶抑制剂和9种HIV-1蛋白酶抑制剂的对接分数，并与一种M的α-酮酰胺抑制剂的对接分数进行比较，最近已证明该α-酮酰胺抑制剂在细胞培养中可抑制SARS-CoV2病毒复制。我们鉴定出8种HCV蛋白酶抑制剂，它们与M活性位点的结合对接分数高于α-酮酰胺抑制剂，这表明这些蛋白酶抑制剂可能有效地结合到M活性位点。这些结果为我们将鉴定出的HCV蛋白酶抑制剂作为SARS-CoV2蛋白酶的抑制剂以及SARS-CoV2病毒复制的抑制剂进行测试提供了理论依据。随后，这些重新利用的药物可作为新冠治疗药物进行评估。
