Organic synthesis and enzymatic assays

项目摘要 有机合成和酶分析 核心1 -阿里，马萨诸塞大学医学院 耐药性是治疗许多病原性感染和癌症的主要限制。 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。由于大量的可用数据，HIV-1蛋白酶是一个独特的模型系统， 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，并制定药物设计策略，以避免 阻力核心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，NMR和抗性所需的蛋白酶抑制剂和类似物 选择研究我们将与计算和结构生物学小组密切合作， 使用多个核心支架的抑制剂，充分利用HIV-1中不同亚位点的相互依赖性 蛋白酶识别我们将进行化学合成的设计抑制剂，并评估其 在针对野生型蛋白酶和耐药变体的酶测定中的活性。这种高度合作 综合方法将有助于阐明耐药机制， 设计更强的抑制剂，不易产生耐药性。

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.