MECHANISTIC ENZYMOLOGY OF HIV PROTEINS, AN APPROACH TO RATIONAL DRUG DESIGN

酶学、化学和酶动力学方法，以及 合成和分析化学正被用于开发新的 靶向逆转录酶（RT）和蛋白酶的药物 HIV-1的酶。 i）方便的连续光谱的设计 正在研究RT的测定。 ii）亲和标记剂 和/或基于机制的抑制剂正在开发，以探测 RT的活性位点。 基团，包括环氧化物和羰基，其是 可能能够与亲核试剂在活性 RT位点已经制备并测试了抗HIV活性， 体外iii）现有资料表明，艾滋病毒蛋白酶 是乙酰基蛋白酶。 潜在抑制剂的合成 这类蛋白酶正在进行中，几种这样的化合物 已被检测出抗艾滋病毒活性。 三、天然产物 从南太平洋海绵中提取的植物提取物， 细胞培养中的HIV。 尽管迄今为止测试的化合物 在体外表现出抗HIV活性，它们可能是 可用作酶抑制剂，并可能产生有价值的信息 关于目标酶的活性位点。

Methods of enzymology, chemical and enzymatic kinetics, and synthetic and analytical chemistry are being used to develop novel agents targeted against the reverse transcriptase (RT) and protease enzymes of HIV-l. i) Design of a convenient continuous spectral assay for RT is being investigated. ii) Affinity labeling agents and/or mechanism-based inhibitors are being developed to probe the active site of RT. Nucleoside analogs that contain functional groups, including an epoxide and a carbonyl group, that are potentially capable of reacting with nucleophiles at the active site of RT have been prepared and tested for anti-HIV activity in vitro. iii) Available information suggests that the HIV protease is an aspartyl protease. Syntheses of potential inhibitors for this class of protease are underway, and several such compounds have been tested for anti-HIV activity. iv) Three natural products derived from South Pacific marine sponges have been tested against HIV in cell culture. Although none of the compounds tested to date have exhibited anti-HIV activity in vitro, they are potentially useful as enzyme inhibitors and may yield valuable information concerning the active sites of the target enzymes.