Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists

Hirokazu Tamamura; Kenichi Hiramatsu; Makiko Mizumoto; Satoshi Ueda; Shuichi Kusano; Shigemi Terakubo; Miki Akamatsu; Naoki Yamamoto; John O. Trent; Zixuan Wang; Stephen C. Peiper; Hideki Nakashima; Akira Otaka; Nobutaka Fujii

doi:10.1039/B306613B

Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists†

Hirokazu Tamamura,*^a Kenichi Hiramatsu,^a Makiko Mizumoto,^a Satoshi Ueda,^a Shuichi Kusano,^b Shigemi Terakubo,^b Miki Akamatsu,^c Naoki Yamamoto,^d John O. Trent,^e Zixuan Wang,^f Stephen C. Peiper,^f Hideki Nakashima,^b Akira Otaka^a and Nobutaka Fujii*^a

Author affiliations

* Corresponding authors

^a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

^b St. Marianna University, School of Medicine, Miyamae-ku, Kawasaki 216-8511, Japan

^c Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

^d Tokyo Medical and Dental University, School of Medicine, Bunkyo-ku, Tokyo 113-8519, Japan

^e James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA

^f Medical College of Georgia, Augusta, GA 30912, USA

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^α-acylation by several benzoic acid derivatives have disclosed a significant relationship between the anti-HIV activity and the Hammett constant (σ) 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.

Organic & Biomolecular Chemistry

Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists†

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Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists

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