Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.

Authors

• Hirokazu Tamamura
• Kenichi Hiramatsu
• a Shuichi Kusano
• Shigemi Terakubo
• Naoki Yamamoto
• John O Trent
• Zixuan Wang
• Stephen C Peiper
• Hideki Nakashima
• Akira Otaka
• Nobutaka Fujii

Publication/Presentation Date

11-7-2003

Abstract

A peptidic CXCR4 antagonist T140 efficiently blocks the entry of T cell line-tropic strains of HIV-1 (X4-HIV-1) into target cells. In this study, a series of T140 derivatives, replacing the basic amino acid residues with Glu (D-Glu) and/or L-citrulline (Cit), were synthesized in order to reduce non-specific binding and cytotoxicity. Among them, TE14011 ([Cit6, D-Glu8]-T140 with the C-terminal amide) exhibited strong anti-HIV activity and low cytotoxicity. TE14011 was found to be stable in mouse serum, but unstable in rat liver homogenate due to the deletion of the N-terminal Arg1-Arg2-L-3-(2-naphthyl)alanine (Nal)3 residues from the parent peptide. N-Terminal acetylation of TE14011 led to the development of a novel lead compound, Ac-TE 14011, which possesses a high selectivity index as well as increased stability in serum and liver homogenate.

Volume

1

Issue

21

First Page

3656

Last Page

3662

ISSN

1477-0520

Published In/Presented At

Tamamura, H., Hiramatsu, K., Kusano, aS., Terakubo, S., Yamamoto, N., Trent, J. O., Wang, Z., Peiper, S. C., Nakashima, H., Otaka, A., & Fujii, N. (2003). Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives. Organic & biomolecular chemistry, 1(21), 3656–3662. https://doi.org/10.1039/b306473p

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

14649896

Department(s)

Administration and Leadership

Document Type

Article