title: Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities.
abstract: Previously, we have identified a highly potent CXCR4 antagonist 2 [cyclo(-D-Tyr1-Arg2-Arg3-Nal4-Gly5-)] and its Arg2 epimer 3 [cyclo(-D-Tyr1-D-Arg2-Arg3-Nal4-Gly5-)] by the screening of cyclic pentapeptide libraries that were designed based on the structure-activity relationship studies on 14-residue peptidic CXCR4 antagonist 1. In the present study, a new series of analogues of 2 and 3 were synthesized to evaluate the influences of peptide side-chain and backbone modification on bioactivities. Based on the Ala-scanning study, in which each residue in 2 and 3 was replaced with Ala having the identical chirality, substitution of Arg3 and Nal4 [Nal = L-3-(2-naphthyl)alanine] with Ala (compounds 6, 7, 10, 11) led to significant loss of the potency, indicating these amino acids are more important contributors to the bioactivity. For the cyclic peptide backbone, several modifications including d/l-Ala or cyclic amino acids substitution at the Gly5 position and sequential N-methylation on amide nitrogens were conducted. Among the analogues, compounds 13 [cyclo(-D-Tyr1-Arg2-Arg3-Nal4-D-Ala5-)] and 32 [cyclo(-D-Tyr1-D-MeArg2-Arg3-Nal4-Gly5-)] were close in potency to the most potent lead 2. NMR and conformational analysis indicated that both of these analogues favor the same backbone conformation as 2, whereas similar analysis of less potent analogues indicates that an altered backbone conformation is favored. The conformational analysis showed that steric repulsion by a 1,3-allylic strain-like effect across the planar peptide bond might contribute to the conformational preferences of cyclic pentapeptides.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Zi-xuan
authors.initials: ZX
authors.lastname: Wang
authors.forename: Takanobu
authors.initials: T
authors.lastname: Araki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cluzeau
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kusano
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; C517799:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-alanyl); C517800:cyclo(tyrosyl-methylarginyl-arginyl-3-(2-naphthyl)alanyl-glycyl); D000409:Alanine