Development of broad-spectrum halomethyl ketone inhibitors against coronavirus main protease 3CL(pro).
Development of broad-spectrum halomethyl ketone inhibitors against coronavirus main protease 3CL(pro).
复制标题
DOI：
10.1111/j.1747-0285.2008.00679.x
复制
发表时间：
2008-07
影响因子：
3
通讯作者：
Freire E
中科院分区：
文献类型：
--
作者：
Bacha U;Barrila J;Gabelli SB;Kiso Y;Mario Amzel L;Freire E
冠状病毒包括一大组具有不同宿主特异性的RNA病毒。SARS冠状病毒（SARS-CoV）等高致病性毒株的出现，以及两种新冠状病毒NL-63和HKU 1的发现，证实了突变和重组的高速率，使它们能够跨越物种障碍并感染新宿主。因此，开发对该家族的几个成员有效的广谱抗病毒药物是非常可取的。这一目标可以通过设计针对靶点的抑制剂来实现，例如主要蛋白酶3CLpro（Mpro），它在所有冠状病毒中高度保守。在这里，来自SARS-CoV的3CLpro被用作主要靶标，以鉴定含有卤甲基酮弹头的一类新的抑制剂。这些化合物对SARS 3CLpro具有高度有效性，Ki值低至300 nm。 其中一种化合物与3CLpro的复合物的晶体结构表明，这种抑制剂在弹头的卤代甲基碳和催化Cys 145之间形成硫醚键。此外，这些化合物的结构活性关系（SAR）研究已经导致了药效团的鉴定，该药效团准确地定义了高亲和力所需的基本分子特征。
Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS‐CoV), and the discovery of two new coronaviruses, NL‐63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad‐spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CLpro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS‐CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with K i’s as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.
登录
查看更多内容
冠状病毒主蛋白酶的结构揭示了甲over依蛋白酶折叠与额外的α-螺旋结构域的组合。
影响因子：
11.4
作者：
Anand, Kanchan;Palm, Gottfried J;Mesters, Jeroen R;Siddell, Stuart G;Ziebuhr, John;Hilgenfeld, Rolf
通讯作者：
Hilgenfeld, Rolf
DOI：
10.1016/s0140-6736(03)13077-2
发表时间：
2003-04-19
期刊：
Lancet (London, England)
影响因子：
--
作者：
Peiris JS;Lai ST;Poon LL;Guan Y;Yam LY;Lim W;Nicholls J;Yee WK;Yan WW;Cheung MT;Cheng VC;Chan KH;Tsang DN;Yung RW;Ng TK;Yuen KY;SARS study group
通讯作者：
SARS study group
DOI：
10.1074/jbc.m310875200
发表时间：
2004-01-16
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fan K;Wei P;Feng Q;Chen S;Huang C;Ma L;Lai B;Pei J;Liu Y;Chen J;Lai L
通讯作者：
Lai L
影响因子：
3.8
作者：
Hegyi, A;Ziebuhr, J
通讯作者：
Ziebuhr, J
影响因子：
2.9
作者：
Barrila, Jennifer;Bacha, Usman;Freire, Ernesto
通讯作者：
Freire, Ernesto