NIMBLE CHEMISTRY TO MATCH HIV PROTEASE EVOLUTION

小分子HIV蛋白酶抑制剂(HIVpr)在两种疾病的治疗中都发挥了核心作用。 在疾病和病毒的进化中实现抗药性。目标的移动性要求 更好地了解实现抵抗的方式以及应对这种情况的能力 通过创造新的药物来克服耐药性机制来改变。 我们提出了一个化学合成和分析的方案，服务于信息流的双向， 将对抗性结构细节的预测转化为用来挑战 进化的系统，并允许进化的蛋白质产生分子抑制物，告诉我们它在哪里 不见了。首先，我们将使用预测或预测的片段来准备新的候选hiv pr抑制剂文库。 显示为结合在靶标的特定位置。这些碎片结构将来自其他实验室 该计划联盟和我们自己的努力，以确定结合元件的多肽为基础的文库。 由此产生的抑制剂将由该计划的其他成员进行测试，并将结果反馈到 持续循环的设计和综合。 除了这种更传统的组合方法外，我们还将允许野生型和突变型的 HIV公关人员用精心挑选的积木组装他们自己的抑制剂，这种技术我们称之为“点击 该方法依赖于所使用的叠氮化物和炔基的独特的化学性质。 在区块之间建立联系，我们之前已经成功地发现了新的 以这种方式合成的蛋白酶活性部位抑制剂。 最后，我们将尝试通过制定和筛选候选人来开辟一个相关的调查领域 结合到作为HIV PR底物的多蛋白裂解位点。文献中的最新报道 提示这可能代表了一种有效的治疗方法，它与我们的 试图了解耐药性的发展。

Small-molecule inhibitors of HIV protease (HIV Pr) have played a central role in both the treatment of the disease and in the evolution of the virus to achieve drug resistance. The moving nature of the target requires greater understanding of the ways in which resistance is achieved, as well as the ability to respond to such changes by creating new drugs to overcome the resistance mechanisms. We propose a program of chemical synthesis and analysis that services both directions of information flow, translating predictions of the structural details of resistance into molecules with which to challenge the evolving system, and allowing the evolving protein to produce molecular inhibitors that tell us where it has gone. First, we will prepare new libraries of candidate HIV Pr inhibitors using fragments either predicted or shown to bind at particular sites of the target. These fragment structures will come from other laboratories in the program consortium and from our own efforts to identify binding elements from peptide-based libraries. The resulting inhibitors will be tested by other members of the program, and the results fed back into the continuing loop of design and synthesis. In addition to this more traditional combinatorial approach, we will also allow wild-type and mutant forms of HIV Pr to assemble their own inhibitors from carefully chosen building blocks in a technique we call "click chemistry in situ." The method relies on the unique chemical properties of the azide and alkyne groups used to make the connections between blocks, and we have previously been successful in uncovering new protease active site inhibitors in this manner. Lastly, we will attempt to open up a connected area of investigation by making and screening candidates for binding to the polyprotein cleavage sites that are the substrates for HIV Pr. Recent reports in the literature suggest that this may represent an effective therapeutic approach, and it has fundamental relevance to our attempts to understand the development of drug resistance.