Progress toward rationally designed small-molecule peptide and peptidomimetic CXCR4 antagonists

Abstract

Over the last five years, X-ray structures of CXC chemokine receptor 4 (CXCR4) in complex with three different ligands (the small-molecule antagonist IT1t, the polypeptide antagonist CVX15, and the viral chemokine antagonist vMIP-II) have been released. In addition to the inherent scientific value of these specific X-ray structures, they (i) provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV-1 gp120); and (ii) serve as valuable templates for further development of small-molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands – based on the X-ray structures of CXCR4 – and the current status of small-molecule peptide and peptidomimetic CXCR4 antagonists.