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 w...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-03, Vol.55 (6), p.2746-2757
Main Authors: Kobayashi, Kazuya, Oishi, Shinya, Hayashi, Ryoko, Tomita, Kenji, Kubo, Tatsuhiko, Tanahara, Noriko, Ohno, Hiroaki, Yoshikawa, Yasushi, Furuya, Toshio, Hoshino, Masaru, Fujii, Nobutaka
Format: Article
Language:English
Subjects:
Alkenes - chemical synthesis
Alkenes - chemistry
Alkenes - pharmacology
Dipeptides - chemistry
HEK293 Cells
Humans
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Conformation
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Peptidomimetics - chemical synthesis
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Radioligand Assay
Receptors, CXCR4 - antagonists & inhibitors
Static Electricity
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2016914