Structure–Activity Relationship Study of a CXC Chemokine Receptor Type 4 Antagonist, FC131, Using a Series of Alkene Dipeptide Isosteres

A structure–activity relationship study on a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr1-Arg2-Arg3-Nal4-Gly5-)], was carried out using a series of alkene isosteres of the d-Tyr1-l/d-Arg2 dipeptide to investigate the binding mode of FC131 and its derivatives with CXCR4. The structure–activity relationships of isostere-containing FC131 analogues were similar to those of the parent FC131 and its derivatives, suggesting that a trans-conformer of the d-Tyr1–Arg2 peptide bond is the dominant contributor to the bioactive conformations of FC131. Although NMR analysis demonstrated that the two conformations of the peptidomimetic containing the d-Tyr1-d-Arg2 isostere are possible, binding-mode prediction indicated that the orientations of the alkene motif within d-Tyr1-MeArg2 peptidomimetics depend on the chirality of Arg2 and the β-methyl group of the isostere unit, which makes the dominant contribution for binding to the receptor. The most potent FC122 [cyclo(-d-Tyr1-d-MeArg2-Arg3-Nal4-Gly5-)] bound with CXCR4 by a binding mode different from that of FC131.