Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents.
Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents.
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DOI：
10.1038/s42003-020-01577-x
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发表时间：
2021-01-20
影响因子：
5.9
通讯作者：
Taval S
中科院分区：
文献类型：
--
作者：
Mody V;Ho J;Wills S;Mawri A;Lawson L;Ebert MCCJC;Fortin GM;Rayalam S;Taval S
新出现的严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染暴发是对公共卫生的重大威胁。由于缺乏SARS-CoV-2特异性药物，其发病率正在增加。在此，我们已经确定了靶向3-糜蛋白酶样蛋白酶（3CLpro）的潜在药物，3CLpro是SARS-CoV-2复制的关键蛋白酶。采用计算分子模拟方法对3987种FDA批准的药物进行筛选，从中选出47种药物，研究其对SARS-CoV-2特异性3CL pro酶的体外抑制作用。我们的研究结果表明，博赛匹韦，奥比他韦，帕利匹韦，替拉那韦，伊维菌素，米卡芬净对3CLpro酶活性表现出抑制作用。100 ns的分子动力学模拟研究表明，伊维菌素可能需要同源二聚体形式的3CLpro酶的抑制活性。总之，这些分子可能有助于开发高度特异性的治疗可行的药物，以抑制SARS-CoV-2复制，无论是单独或与其他SARS-CoV-2病毒靶点特异性药物联合使用。在这里，作者确定了靶向3-糜蛋白酶样蛋白酶（3CLpro）的潜在药物，3CLpro是SARS-CoV-2复制的关键蛋白酶。他们发现，诸如伊维菌素和米卡芬净等脱靶抑制剂抑制3CLpro酶活性，这表明这些分子可以构成抑制SARS-CoV-2复制的有用疗法。
Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets. Here, the authors identify potential drugs that target 3-chymotrypsin like protease (3CLpro), which is a pivotal protease for the replication of SARS-CoV-2. They found that off-target inhibitors such as ivermectin and micafungin inhibit 3CLpro enzyme activity, suggesting that these molecules could constitute useful therapies to inhibit SARS-CoV-2 replication.
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DOI：
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