title: Structure-activity relationship study of a CXC chemokine receptor type 4 antagonist, FC131, using a series of alkene dipeptide isosteres.
abstract: A structure-activity relationship study on a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)], was carried out using a series of alkene isosteres of the d-Tyr(1)-l/d-Arg(2) 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-Tyr(1)-Arg(2) 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-Tyr(1)-d-Arg(2) isostere are possible, binding-mode prediction indicated that the orientations of the alkene motif within d-Tyr(1)-MeArg(2) peptidomimetics depend on the chirality of Arg(2) 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-Tyr(1)-d-MeArg(2)-Arg(3)-Nal(4)-Gly(5)-)] bound with CXCR4 by a binding mode different from that of FC131.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kubo
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanahara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.forename: Masaru
authors.initials: M
authors.lastname: Hoshino
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D004151:Dipeptides; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D019718:Receptors, CXCR4; C496951:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl)