HIV-1 Protease Inhibitors with Extended Conformations

具有扩展构象的 HIV-1 蛋白酶抑制剂

• 批准号: 6590944
• 负责人: MARK L MCLAUGHLIN
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590944
• 关键词: antiAIDS agent; conformation; dipeptides; drug design /synthesis /production; enzyme activity; protease inhibitor; synthetic peptide

DESCRIPTION (provided by applicant): Since proteases including HIV-1 protease bind to their peptide/protein substrates in extended conformations, protease inhibitors constrained to form extended conformations are likely to produce very active protease inhibitors because they are pre-organized to form favorable interactions with the enzyme environment immediately surrounding its active site. This hypothesis will be tested by synthesizing a family of structurally related dipeptide-like molecules that are constrained to adopt the extended conformation. The activity and specificity of these novel protease inhibitors will be compared with currently available HIV-1protease inhibitors. The dipeptide-like molecules will be used as a central core and peripheral groups will be attached to the N- and C- termini that are selected by structural analogy with the most successful currently available HIV-1 protease inhibitors. These hybrid structures will be tested for HIV-1 protease inhibitor activity and specificity to guide optimization of these parameters via an iterative process. Nanomolar HIV-1 protease inhibitors with good specificity are currently used as drugs. But, it is likely that the approach described herein will uncover super-potent lead compounds that inhibit HIV-1 protease at pico-, femto-, or perhaps even sub-femtomolar concentrations. If these inhibitors can also be designed with high specificity and the other issues associated with drug development that are far outside the scope of this small grant can be addressed, then the side effects of long-term treatment will likely be reduced because the dose can be reduced. Furthermore, super-potent drugs could significantly reduce the cost per day of treatment, which is a huge issue for HIV/AIDS treatment in the developing world.

描述（由申请人提供）：由于包括 HIV-1 蛋白酶在内的蛋白酶以延伸构象与其肽/蛋白质底物结合，因此限制形成延伸构象的蛋白酶抑制剂可能产生非常活性的蛋白酶抑制剂，因为它们被预先组织以形成有利的相互作用酶环境紧邻其活性位点。该假设将通过合成一系列结构相关的二肽样分子来检验，这些分子被限制采用扩展构象。这些新型蛋白酶抑制剂的活性和特异性将与目前可用的 HIV-1 蛋白酶抑制剂进行比较。二肽样分子将用作中心核心，而外围基团将连接至 N 端和 C 端，这些基团通过与目前最成功的 HIV-1 蛋白酶抑制剂的结构类比来选择。这些混合结构将进行 HIV-1 蛋白酶抑制剂活性和特异性测试，以通过迭代过程指导这些参数的优化。目前，纳摩尔HIV-1蛋白酶抑制剂具有良好的特异性，被用作药物。但是，本文描述的方法很可能会发现超强的先导化合物，可以在皮摩尔、飞摩尔、甚至亚飞摩尔浓度下抑制 HIV-1 蛋白酶。如果这些抑制剂也可以设计得具有高特异性，并且可以解决远远超出这笔小额资助范围的与药物开发相关的其他问题，那么长期治疗的副作用可能会减少，因为剂量可以减少减少。此外，超强效药物可以显着降低每日治疗成本，这是发展中国家艾滋病毒/艾滋病治疗的一个大问题。