Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses
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DOI：
10.1128/jvi.01348-12
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发表时间：
2012-11-01
影响因子：
5.4
通讯作者：
Chang, Kyeong-Ok
中科院分区：
文献类型：
--
作者：
Kim, Yunjeong;Lovell, Scott;Chang, Kyeong-Ok
系统发育分析表明，一些正义RNA病毒可以被归类为小核糖核酸病毒样超簇，包括小核糖核酸病毒，杯状病毒和冠状病毒。这些病毒具有3C或3C样蛋白酶（分别为3Cpro或3CLpro），其含有典型的胰凝乳蛋白酶样折叠和具有Cys残基作为亲核体的催化三联体（或二联体）。3Cpro或3CLpro的保守关键位点可作为设计针对超簇中多种病毒的广谱抗病毒药物的有吸引力的靶标。我们先前报道了基于结构的设计和合成的有效的蛋白酶抑制剂的诺瓦克病毒（NV），杯状病毒科的成员。我们在此报道了具有不同弹头的共同二肽基残基的三种化合物的广谱抗病毒活性，即，醛（GC 373）、亚硫酸氢盐加合物（GC 376）和α-酮酰胺（GC 375），针对属于超簇的病毒。所有化合物对大多数测试的病毒都是高度有效的，在基于酶和/或细胞的测定中，半数最大抑制浓度在高纳摩尔或低微摩尔范围内，并且具有高治疗指数。我们还报告了NV 3CLpro-，脊髓灰质炎病毒3Cpro-和传染性胃肠炎病毒3CLpro-GC 376抑制剂复合物的高分辨率X射线共晶结构，该复合物共价结合到相应蛋白酶催化位点的亲核Cys残基上。我们的结论是，这些化合物有可能被开发为针对一个单一的病毒或多个病毒的小核糖核酸病毒样超簇靶向3Cpro或3CLpro的抗病毒治疗。
Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme-and/ or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro-GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.