Humblet C C, Lunney E A, Buckheit R W, Doggett C, Wong R, Antonucci T K
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Antiviral Res. 1993 May;21(1):73-84. doi: 10.1016/0166-3542(93)90068-t.
The human immunodeficiency virus (HIV-1), associated with the AIDS (acquired immunodeficiency syndrome) epidemic, encodes an aspartyl protease that is essential for polyprotein processing in the virus (Navia et al., 1989). It has been demonstrated that inactivation of the protease either catalytically or by an inhibitor prevents infectious virion formation (Kohl et al., 1988; Darke et al., 1989). The acquired knowledge of key molecular interactions occurring between inhibitors and aspartyl proteases, as well as the structural similarities between HIV-1 protease and human renin was used to rationally select candidates for HIV-1 screening from the pool of analogs designed as renin inhibitors. A minimal number of chosen compounds were tested in an HIV-1 protease assay system. Two structurally novel peptides emerged as potent enzymatic protease inhibitors. This study highlights the selection process and characterizes the antiviral properties of the two novel analogs.
与艾滋病（获得性免疫缺陷综合征）流行相关的人类免疫缺陷病毒1型（HIV-1）编码一种天冬氨酸蛋白酶，该酶对于病毒中的多蛋白加工至关重要（纳维亚等人，1989年）。已证明，通过催化作用或使用抑制剂使该蛋白酶失活可阻止感染性病毒粒子的形成（科尔等人，1988年；达克等人，1989年）。基于对抑制剂与天冬氨酸蛋白酶之间关键分子相互作用的了解，以及HIV-1蛋白酶与人类肾素之间的结构相似性，从设计为肾素抑制剂的类似物库中合理选择用于HIV-1筛选的候选物。在HIV-1蛋白酶检测系统中对少量选定的化合物进行了测试。两种结构新颖的肽成为有效的酶促蛋白酶抑制剂。本研究突出了筛选过程，并对这两种新型类似物的抗病毒特性进行了表征。
