Design and synthesis of novel cyclopentapeptide antagonist for the chemokine receptor CXCR4

Abstract

CXCR4 is a GPCR that by activation of its ligand CXCL12 is involved in the pathology of several diseases, examples being cancer and rheumatoid arthritis. It has also shown to play a crucial role for HIV-1 entry into T-cells and the development of AIDS. Several cyclopentapeptides (CPPs) based on the sequence D-Tyr-Arg-Arg-2-Nal-Gly of the lead compound FC131 have shown to have antagonistic activity. These CCPs are therefore targets for drug research. In this thesis a previously published 3-point pharmacophore for these CCPs is reproduced and a new 4-point pharmacophore is presented. Structural similarities of low-energy conformations of CPPs that fit these pharmacophores have been identified. A set of new conformational stabilized CPPs based on these findings have been designed and synthesized. A set of citrulline based analogs of FC131 have been synthesized as they will serve as probes to determine the nature of the Arg residues interaction with CXCR4