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.
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