3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.
3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.
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DOI：
10.1126/scitranslmed.abc5332
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发表时间：
2020-08-19
影响因子：
17.1
通讯作者：
Chang KO
中科院分区：
文献类型：
--
作者：
Rathnayake AD;Zheng J;Kim Y;Perera KD;Mackin S;Meyerholz DK;Kashipathy MM;Battaile KP;Lovell S;Perlman S;Groutas WC;Chang KO
优化的小分子3c样蛋白酶抑制剂在细胞培养和小鼠模型中都显示出对人类冠状病毒的效力。冠状病毒3c样蛋白酶（3CLpro）是有吸引力的治疗靶点，因为它们在冠状病毒复制中起着至关重要的作用。Rathnayake等人现在报道了一系列优化的冠状病毒3CLpro抑制剂，可阻断人类冠状病毒MERS-CoV和SARS-CoV-2在培养细胞中的复制。将一种先导化合物应用于中东呼吸综合征冠状病毒小鼠模型显示出概念验证的有效性。这些发现表明，应该进一步研究这种先导化合物作为治疗人类冠状病毒感染的潜在药物。致病性冠状病毒是对全球公共卫生的重大威胁，例如严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）和新出现的2019冠状病毒病（COVID-19）病原体SARS-CoV-2。本文描述了一系列冠状病毒3c样蛋白酶（3CLpro）抑制剂的结构导向优化，3CLpro是病毒复制所必需的酶。优化后的化合物对几种人类冠状病毒（包括MERS-CoV、SARS-CoV和SARS-CoV-2）在酶检测和以Huh-7和Vero E6细胞系为基础的细胞检测中均有效。两种选定的化合物在培养的原代人气道上皮细胞中对SARS-CoV-2表现出抗病毒作用。在MERS-CoV感染小鼠模型中，在病毒感染后1天给予先导化合物可将存活率从0提高到100%，并降低肺病毒滴度和肺组织病理学。这些结果表明，该系列化合物具有进一步开发用于人类冠状病毒抗病毒药物的潜力。
Optimized small-molecule 3C-like protease inhibitors show potency against human coronaviruses in both cell culture and a mouse model. Coronavirus 3C-like proteases (3CLpro) are attractive therapeutic targets because they play a vital role in coronavirus replication. Rathnayake et al. now report a series of optimized coronavirus 3CLpro inhibitors that blocked replication of the human coronaviruses MERS-CoV and SARS-CoV-2 in cultured cells. Administration of a lead compound to a MERS-CoV mouse model demonstrated proof-of-concept efficacy. These findings suggest that this lead compound should be investigated further as a potential therapeutic for human coronavirus infection. Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
6.7
作者：
Galasiti Kankanamalage AC;Kim Y;Damalanka VC;Rathnayake AD;Fehr AR;Mehzabeen N;Battaile KP;Lovell S;Lushington GH;Perlman S;Chang KO;Groutas WC
通讯作者：
Groutas WC
影响因子：
5.4
作者：
Kim, Yunjeong;Shivanna, Vinay;Chang, Kyeong-Ok
通讯作者：
Chang, Kyeong-Ok
影响因子：
7.3
作者：
Dragovich, PS;Prins, TJ;Worland, ST
通讯作者：
Worland, ST