Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity.

Authors

• H Tamamura
• M Sugioka
• Y Odagaki
• A Omagari
• Y Kan
• S Oishi
• H Nakashima
• N Yamamoto
• S C Peiper
• N Hamanaka
• A Otaka
• N Fujii

Publication/Presentation Date

2-12-2001

Abstract

We report the solution structure of T140, a truncated polyphemusin peptide analogue that efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 through its specific binding to a chemokine receptor, CXCR4. Nuclear magnetic resonance analysis and molecular dynamic calculations revealed that T140 has a rigidly structured conformation constituted by an antiparallel beta-sheet and a type II' beta-turn. A protuberance is formed on one side of the beta-sheet by the side-chain functional groups of the three amino acid residues (L-3-(2-naphthyl)alanine, Tyr5 and Arg14), each of which is indispensable for strong anti-HIV activity. These findings provide a rationale to dissect the structural basis for the ability of this compound to block the interaction between CXCR4 and envelope glycoproteins from T-tropic strains of HIV-1.

Volume

11

Issue

3

First Page

359

Last Page

362

ISSN

0960-894X

Published In/Presented At

Tamamura, H., Sugioka, M., Odagaki, Y., Omagari, A., Kan, Y., Oishi, S., Nakashima, H., Yamamoto, N., Peiper, S. C., Hamanaka, N., Otaka, A., & Fujii, N. (2001). Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity. Bioorganic & medicinal chemistry letters, 11(3), 359–362. https://doi.org/10.1016/s0960-894x(00)00664-8

Disciplines

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

PubMedID

11212110

Department(s)

Administration and Leadership

Document Type

Article