HIV-1 Protease Inhibitors with Extended Conformations

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它们的肽/蛋白质底物结合，限制形成延伸构象的蛋白酶抑制剂可能产生非常活跃的蛋白酶抑制剂，因为它们被预先组织成与活性位点周围的酶环境形成有利的相互作用。这一假设将通过合成一系列结构相关的二肽样分子来验证，这些分子被限制采用扩展的构象。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，外周基团将连接到N-和C-末端，这些末端通过与目前最成功的HIV-1蛋白酶抑制剂的结构类比选择。这些混合结构将测试HIV-1蛋白酶抑制剂的活性和特异性，以指导通过迭代过程优化这些参数。具有良好特异性的纳米级HIV-1蛋白酶抑制剂目前被用作药物。但是，本文描述的方法很可能会发现在微摩尔、毫摩尔甚至亚毫摩尔浓度下抑制HIV-1蛋白酶的超强先导化合物。如果这些抑制剂也能被设计成具有高特异性，那么与药物开发相关的其他问题就能得到解决，这些问题远远超出了这笔小额资助的范围，那么长期治疗的副作用可能会减少，因为剂量可以减少。此外，超级强效药物可以显著降低每天的治疗费用，这是发展中国家艾滋病毒/艾滋病治疗的一个巨大问题。

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.