Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19
Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19
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DOI：
10.1021/acs.jmedchem.0c01063
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发表时间：
2020-11-12
影响因子：
7.3
通讯作者：
Taggart, Barbara
中科院分区：
文献类型：
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作者：
Hoffman, Robert L.;Kania, Robert S.;Taggart, Barbara
2019 年出现的新型冠状病毒病 COVID-19 是由病毒 SARS CoV-2 引起的，因其与 2002 年引起严重急性呼吸综合征 (SARS) 的 SARS CoV-1 基因相似而得名。两种 SARS 冠状病毒基因组都编码两个重叠的大多蛋白，这些多蛋白在翻译后加工步骤中被 3C 样半胱氨酸蛋白酶 (3CL(pro)) 在特定位点切割，这对冠状病毒复制至关重要。 CoV-1 和 CoV-2 病毒的 3CL(pro) 序列在执行蛋白质裂解的催化结构域中 100% 相同。一项专注于发现可逆和不可逆酮基 SARS CoV-1 3CL(pro) 抑制剂的研究工作，采用 X 射线晶体学解析的配体-蛋白酶结构，鉴定了 3 和 4。临床前实验表明 4 (PF-00835231) 是 CoV-2 3CL(pro) 的有效抑制剂，具有合适的药物特性，可进一步开发为 COVID-19 的静脉注射治疗药物。
The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL(pro)) in a post-translational processing step that is critical for coronavirus replication. The 3CL(pro) sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL(pro) employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL(pro) with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.