Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.
Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.
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DOI：
10.1016/j.ejmech.2018.03.004
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发表时间：
2018-04-25
影响因子：
6.7
通讯作者：
Groutas WC
中科院分区：
文献类型：
--
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
目前没有批准的疫苗或小分子治疗剂可用于预防或治疗中东呼吸综合征冠状病毒（MERS-CoV）感染。MERS-CoV 3CL蛋白酶是病毒复制所必需的;因此，它是一个有吸引力的靶标，为开发用于对抗MERS-CoV的小分子治疗剂提供了潜在有效的手段。我们在本文中描述了一类新型MERS-CoV 3CL蛋白酶抑制剂的结构指导设计和评价，所述新型MERS-CoV 3CL蛋白酶抑制剂包含哌啶部分作为非常适合于利用有利的亚位点结合相互作用以获得最佳药理学活性和PK性质的设计元素。使用X射线晶体学阐明了化合物的作用机制和与结合相关的结构决定因素。进行了一类新型中东呼吸综合征冠状病毒（MERS-CoV）3CL蛋白酶抑制剂的结构导向设计。一个哌啶部分被用作设计元素的拟肽抑制剂的合成，利用与酶S3-S4亚位点的相互作用。通过X射线晶体学研究验证了抑制剂设计原理。X射线晶体学证实了抑制剂的作用机制。
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography. The structure-guided design of a new class of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 3CL protease inhibitors was performed. A piperidine moiety was used as a design element in the synthesis of peptidomimetic inhibitors that exploit interactions with the enzyme S3-S4 subsites. The inhibitor design rationale was validated by X-ray crystallographic studies. X-ray crystallography confirmed the mechanism of action of the inhibitors.
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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
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
影响因子：
5.4
作者：
Kim, Yunjeong;Lovell, Scott;Chang, Kyeong-Ok
通讯作者：
Chang, Kyeong-Ok
DOI：
10.1073/pnas.1407087111
发表时间：
2014-10-21
影响因子：
11.1
作者：
Millet, Jean Kaoru;Whittaker, Gary R.
通讯作者：
Whittaker, Gary R.