title: Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists.
abstract: A CXCR4 antagonistic peptide, T140, and its bio-stable analogs, such as Ac-TE14011, were previously developed. These peptides inhibit the entry of T cell line-tropic strains of HIV-1 (X4-HIV-1) into T cells. Herein, a series of TE14011 analogs having modifications in the N-terminal region were synthesized to develop effective compounds with increased biostability. Among these analogs, 4F-benzoyl-TE14011 (TF14013) showed the strongest anti-HIV activity derived from CXCR4-antagonism, suggesting that a 4-fluorobenzoyl moiety at the N-terminus of T140 analogs constitutes a novel T140-based pharmacophore for CXCR4 antagonists. Structure-activity relationship (SAR) studies on TE14011 analogs with N(alpha)-acylation by several benzoic acid derivatives have disclosed a significant relationship between the anti-HIV activity and the Hammett constant (sigma) of substituted benzoic acids. TF14013 was found to be stable in mouse serum, but not completely stable in rat liver homogenate due to deletion of the C-terminal Arg14-NH2 from the parent peptide. This biodegradation was completely suppressed by N-alkyl-amidation at the C-terminus. Taken together, the enhancement of the T140-based pharmacophores led to development of a novel CXCR4 antagonist, 4F-benzoyl-TE14011-Me (TF14013-Me), which has very high anti-HIV activity and increased biostability.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kusano
authors.forename: Shigemi
authors.initials: S
authors.lastname: Terakubo
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D002942:Circular Dichroism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D009842:Oligopeptides; D019718:Receptors, CXCR4; C116977:T140 peptide