DESIGN, SYNTHESIS & NMR CHARACTERIZATION OF FLUORINATED HIV PROTEASE INHIBITOR

设计、合成

• 批准号: 2574400
• 负责人: R E LONDON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/2574400
• 关键词: AIDS; HIV envelope protein gp120; HIV infections; active sites; antiAIDS agent; antiviral agents; aspirin; drug design /synthesis /production; drug screening /evaluation; enzyme activity; intermolecular interaction; nuclear magnetic resonance spectroscopy; pepsin; pharmacokinetics; phenylalanine analog; protease inhibitor; purine nucleoside phosphorylase; virus protein

Initial work on this protein was designed to utilize fluorinated analogs of the cyclic urea inhibitors of HIV-protease originally pioneered by DuPont-Merck and more recently evaluated by Abbott Labs. It was decided, however, that it would be useful to obtain a more basic understanding of the nature of the active site and, since the protease is in relatively short supply, most of the work over the past year has focused on the aspartyl protease, pepsin. In addition to being a member of the aspartyl protease family, there is significant homology between the active sites of the pepsin and HIV protease, as is apparent from the observation that pepsin inhibitors such as acetyl pepstatin are also fairly good inhibitors of the protease. Previously studied inhibitors of pepsin include peptides containing the statine residue ([3S,4S]-4-amino-3- hydroxy-6-methylhepatnoic acid), peptide aldehydes such as N-Ac-Leu-Val- Phenylalaninal, and aliphatic alcoholes. NMR studies of the interaction of these inhibitors with pepsin are in progress. A combination of NMR and activity studies has suggested a new class of inhibitors for this type of enzyme, which are currently under evaluation. Pharmacological modification of viral proteins, particularly the viral coat protein, represents a useful approach to eliciting antibodies against the modified protein. Aspirin is the most common pharmacological acetylating agent, with widely varying specificity. We have recently proposed using aspirin to modify the viral coat protein in order to study the specificity and kinetics of this modification. Initial work will utilize peptides derived from gp120.

对这种蛋白质的初步研究旨在利用氟化类似物 HIV蛋白酶的环脲抑制剂最初是由 DuPont-Merck和最近由Abbott Labs进行的评估。 决定了， 然而，最好能对下列问题有一个更基本的了解： 活性位点的性质，并且由于蛋白酶相对 由于供应短缺，过去一年的大部分工作都集中在 乙酰蛋白酶，胃蛋白酶。 除了作为一个成员的Escheryl 蛋白酶家族，活性位点之间存在显著的同源性 胃蛋白酶和HIV蛋白酶，从观察中可以明显看出， 胃蛋白酶抑制剂如乙酰胃蛋白酶抑制剂也相当好 蛋白酶的抑制剂。 先前研究的胃蛋白酶抑制剂 包括含有他汀残基的肽（[3S，4S]-4-氨基-3- 羟基-6-甲基庚烯酸）、肽醛如N-Ac-Leu-Val- 苯丙氨酸和脂肪醇。 相互作用的NMR研究 这些抑制剂与胃蛋白酶的研究正在进行中。 核磁共振结合 活性研究已经提出了一类新的抑制剂 目前正在评估中的酶的类型。 病毒蛋白的药理学修饰，特别是病毒蛋白的药理学修饰 外壳蛋白，代表了一个有用的方法来引发抗体 对修饰蛋白质的攻击 阿司匹林是最常见的药物 乙酰化剂，具有广泛变化的特异性。 我们最近 建议使用阿司匹林修饰病毒外壳蛋白，以研究 这种修饰的特异性和动力学。 初步工作将 利用来自GP 120的肽。