The herpesvirus protease: mechanistic studies and discovery of inhibitors of the human cytomegalovirus protease.

Drug design and discovery Pub Date : 1997-05-01
D L Flynn, D P Becker, V M Dilworth, M K Highkin, P J Hippenmeyer, K A Houseman, L M Levine, M Li, A E Moormann, A Rankin, M V Toth, C I Villamil, A J Wittwer, B C Holwerda
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Abstract

The herpesvirus protease is a recently identified enzyme which is essential for viral replication. It is found in all herpesviruses and offers a new molecular target for therapeutic intervention. Its genomic structure has recently been described and consists of a large open reading frame which encodes a fusion protein containing an amino-terminal protease domain in-frame with a carboxyl-terminal "assembly protein-like" domain. Auto-processing releases the amino-terminal protease as a maturational enzyme. The herpesvirus protease has been characterized as a novel serine protease. Four surface accessible sulfhydryl groups have been identified in the human cytomegalovirus (HCMV) protease. Utilizing a fluorogenic DABCYL-EDANS substrate assay, directed screening has identified a class of sulfhydryl-modifying benzimidazolylmethyl sulfoxides which inhibits recombinant HCMV protease. Site-directed mutagenesis studies suggest oxidative modification of surface-accessible HCMV protease Cys138 (and possibly Cys161) by this class of inhibitors. The benzimidazolylmethyl sulfoxide 1 inhibits HCMV protease (IC50 = 1.9 microM), exhibits selectivity vs. mammalian serine proteases, and exhibits antiviral activity in an HCMV infected cell culture assay.

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疱疹病毒蛋白酶:人巨细胞病毒蛋白酶抑制剂的机制研究和发现。
疱疹病毒蛋白酶是最近发现的一种对病毒复制至关重要的酶。它存在于所有疱疹病毒中,为治疗干预提供了新的分子靶点。它的基因组结构最近被描述,由一个大的开放阅读框组成,该阅读框编码一个融合蛋白,在框架内包含一个氨基端蛋白酶结构域和一个羧基端“组装蛋白样”结构域。自动加工释放作为成熟酶的氨基末端蛋白酶。疱疹病毒蛋白酶是一种新型丝氨酸蛋白酶。在人巨细胞病毒(HCMV)蛋白酶中发现了四个表面可接近的巯基。利用荧光DABCYL-EDANS底物测定,定向筛选鉴定了一类抑制重组HCMV蛋白酶的巯基修饰苯并咪唑甲基亚砜。定点诱变研究表明,这类抑制剂可以氧化修饰表面可达的HCMV蛋白酶Cys138(也可能是Cys161)。苯并咪唑基甲基亚砜1抑制HCMV蛋白酶(IC50 = 1.9微米),对哺乳动物丝氨酸蛋白酶表现出选择性,并在HCMV感染细胞培养实验中表现出抗病毒活性。
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