INHIBITION OF HIV-1 REPLICATION BY C2 SYMMETRIC HIV PROTEASE INHIBITORS

C2 对称 HIV 蛋白酶抑制剂对 HIV-1 复制的抑制

• 批准号: 3774654
• 负责人: H MITSUYA
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774654
• 关键词: 2'3' dideoxynucleoside; antiviral agents; combination chemotherapy; dimer; drug screening /evaluation; genetic strain; human immunodeficiency virus 1; peptide analog; protease inhibitor; tissue /cell culture; virus protein; virus replication

Human immunodeficiency virus (HIV) codes an aspartic protease which is indispensable for proper virion assembly and maturation. This virus- specific protease mediates crucial proteolytic processing of certain viral protein precursors at a late stage in the replication of HIV. This process is essential for the maturation of newly-assembled virus particles into infectious virions. Indeed, inactivation of HIV protease by site-directed mutation in the protease gene results in the production of immature, non- infectious viral particles. The design of HIV-1 protease inhibitors based on the transition state mimetic concept has led to the generation of a variety of peptide derivatives highly active against viral replication in vitro. Two-fold (C2) symmetry-based inhibitors of HIV protease represent another unique class of potent HIV protease inhibitors which were designed to correspond to the C2 symmetric active site structure of the HIV protease homodimer. One such inhibitor, A77003, which has considerable aqueous solubility, has been shown to have a broad-spectrum of antiretroviral activity against both HIV-1 and HIV-2 types, including AZT- insensitive HIV-1 variants in vitro in a variety of human target cells.

人免疫缺陷病毒（HIV）编码天冬氨酸蛋白酶， 是病毒体组装和成熟所必需的。这种病毒- 特定蛋白酶介导某些病毒的关键蛋白水解加工 蛋白质前体在艾滋病毒复制的后期阶段。这个过程 对于新组装的病毒颗粒成熟成 传染性病毒粒子。事实上，通过定点突变使HIV蛋白酶失活， 蛋白酶基因的突变导致产生不成熟的、非- 传染性病毒颗粒HIV-1蛋白酶抑制剂的设计 关于过渡态模拟的概念导致了 多种肽衍生物对病毒复制具有高度活性， 体外基于双重（C2）乙酰基的HIV蛋白酶抑制剂代表 另一类独特的强效HIV蛋白酶抑制剂， 对应于HIV的C2对称活性位点结构 蛋白酶同源二聚体。一种这样的抑制剂，A77003，其具有相当大的 水溶性，已被证明具有广谱的 抗艾滋病毒1型和艾滋病毒2型的抗逆转录病毒活性，包括AZT- 不敏感的HIV-1变体在体外在各种人靶细胞中。