Structure-activity relationship study of a CXC chemokine receptor type 4 antagonist, FC131, using a series of alkene dipeptide isosteres

Article abstract of DOI:10.1021/jm2016914

A structure-activity relationship study on a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr¹-Arg ²-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-Arg ³-Nal⁴-Gly⁵-)] bound with CXCR4 by a binding mode different from that of FC131.