Organic synthesis and enzymatic assays

项目摘要 有机合成与酶促分析 核心1-阿里，加州大学马萨诸塞州医学院 耐药性是许多病原体感染和癌症治疗的主要限制因素。 了解耐药性的机制并制定避免耐药性的策略可能会导致 更有效的治疗方法。由于现有数据过多，HIV-1蛋白水解酶是一种独特的模型系统 研究耐药机制。在这个高度跨学科的项目中，我们的目标是阐明 HIV-1蛋白酶耐药的分子机制及药物设计策略 抵抗。核心1将为计划项目的成员提供药物化学支持。我们 将合成共结晶、ITC、核磁共振和抗性所需的蛋白酶抑制剂和类似物 选拔研究。我们将与计算和结构生物学小组密切合作，设计新的 使用多个核心支架的抑制剂，充分利用HIV-1不同亚基之间的相互依赖 蛋白酶识别。我们将进行设计的缓蚀剂的化学合成并对其进行评价 野生型蛋白水解酶和耐药变异体的酶活性测定。这种高度协作性 而综合的方法将有助于阐明耐药性的机制并提供策略 设计更强大的抑制剂，减少对耐药性的敏感性。

Project Summary Organic synthesis and enzymatic assays Core 1 - Ali, UMASS Medical School Drug resistance is a major limitation in the treatment of many pathogenic infections and cancers. Understanding the mechanisms of drug resistance and developing strategies to avoid resistance could lead to more effective treatments. Due to the plethora of available data, HIV-1 protease is a unique model system to study the mechanisms of drug resistance. In this highly interdisciplinary Program Project, we aim to elucidate the molecular mechanisms of drug resistance in HIV-1 protease and develop drug design strategies to avoid resistance. The Core 1 will provide medicinal chemistry support to the members of the Program Project. We will synthesize protease inhibitors and analogues required for co-crystallization, ITC, NMR, and resistance selection studies. We will work closely with the computational and structural biology groups to design new inhibitors using multiple core scaffolds that fully leverage the interdependence of different sub-sites in HIV-1 protease recognition. We will carry out the chemical synthesis of designed inhibitors and evaluate their activities in enzymatic assays against wild-type protease and drug-resistant variants. This highly collaborative and integrated approach will help elucidate the mechanisms of drug resistance and provide strategies to design more robust inhibitors less susceptible to drug resistance.