AR COBRE: DRUG DISCOVERY AND DESIGN: HIV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个项目的目标是开发和使用我们新的Calkyl-Calkyl交叉偶联方法来准备一个潜在的趋化因子受体CCR5拮抗剂的文库。已有研究表明，HIV-1对巨噬细胞、单核细胞和T细胞的感染是通过与趋化因子受体CCR5的相互作用而介导的。然而，由于CCR5不存在晶体结构，基于蛋白质结构的CCR5拮抗剂设计一直进展缓慢。我们在发现与C(SP3)键操纵相关的新的催化和化学计量反应方面取得了实质性进展，我们计划使用这一方法学来构建阻断HIV-I gp120与CCR5结合的进入抑制剂。授权期的具体目标包括：1)使用我们的烷基-烷基交叉偶联方法快速合成新的化合物衍生物，这些化合物是趋化因子受体活性的调节剂。2)通过确定配体修饰对C(SP3)-C(SP3)交叉偶联催化的速率、范围和机理的影响，优化了高通量方法的方法学。3)开发烷基亲电试剂的Heck反应，以增加可用于文库合成的底物范围。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this project are to develop and use our new Calkyl-Calkyl cross-coupling methodology for the preparation of a library of potential ?-chemokine receptor CCR5 antagonists. It has been shown that HIV-1 infection of macrophages, monocytes, and T-cells is mediated by interaction with the ?-chemokine receptor CCR5. However, as no crystal structure of CCR5 exists, a protein structure-based CCR5 antagonist design has been slow to develop. We have made substantial progress in discovering new catalytic and stoichiometric reactions related to the manipulation of C(sp3) bonds, and we plan to use this methodology to build entry inhibitors that block the binding of HIV-I gp120 to CCR5. Specific aims for the grant period include: 1) Employing our alkyl-alkyl cross-coupling methodology to rapidly synthesize new derivatives of compounds which are modulators of chemokine receptor activity. 2) Optimizing the methodology for our high-throughput approach by determining the effects of ligand modification on the rates, scope, and mechanism of C(sp3)-C(sp3) cross-coupling catalysis. 3) Developing Heck-type reactions of alkyl electrophiles in order to increase the range of substrates that can be used in the library synthesis.