Selective nonpeptidic inhibitors of herpes simplex virus type 1 and human cytomegalovirus proteases

被引:6
作者
Matsumoto, M [1 ]
Misawa, S [1 ]
Chiba, N [1 ]
Takaku, H [1 ]
Hayashi, H [1 ]
机构
[1] Japan Energy Corp, Pharmaceut & Bioltechnol Lab, Toda, Saitama 3358502, Japan
关键词
HSV-1; protease; HCMV protease; selective inhibitor; dihydroxynaphthalene; naphthoquinone; competitive inhibitor;
D O I
10.1248/bpb.24.236
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The proteases encoded by herpesviruses including herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) are attractive targets for antiviral drug development because of their important roles in viral replication, We randomly screened a chemical compound library for inhibitory activity against HSV-1 protease. 1,4-Dihydroxynaphthalene and three naphthoquinones were found to be potent inhibitors of HSV-1 protease with IC50 values of 6,4 to 16.9 muM. Inhibitory mode analysis of the compounds against HSV-1 protease suggested that, in spite of structural similarities, only 1,4-dihydroxy naphthalene was a competitive inhibitor, whereas the three naphthoquinones were noncompetitive inhibitors, Among all assayed dihydroxynaphthalene derivatives in the chemical compound library; 1,4-dihydroxynaphthalene proved to be the most potent inhibitor of HSV-1 protease, Therefore, the two hydroxyl groups located at positions 1 and 1 on the naphthalene structure seemed essential for exertion of a potent inhibitory activity against HSV-1 protease, In addition, we have found that these compounds are also potent inhibitors of HCMV protease with extremely low micromolar IC50 values. This differed from the results of inhibitory mode analysis of HSV-1 protease, 1,4-dihydroxynaphthalene was a noncompetitive inhibitor of HCMV protease, and three naphthoquinones were competitive inhibitors, These compounds showed no effective inhibitory activity. against several mammalian serine proteases (trypsin, chymotrypsin, kallikrein, plasmin, thrombin and Factor Xa) at 100 muM. These results suggest that 1,4-dihydroxynaphthalene and three naphthoquinones mag be useful in the development of nonpeptidic antiherpesvirus agents.
引用
收藏
页码:236 / 241
页数:6
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