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

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 recept or, CXCR4. Nuclear magnetic resonance analysis and molecular dynamic calcul ations revealed that T140 has a rigidly structured conformation constituted by an antiparallel beta -sheet and a type II' beta -turn. A protuberance i s 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(3), Tyr(5) and A rg(14)), each of which is indispensable for strong anti-HIV activity. These findings provide a rationale to dissect the structural basis for the abili ty of this compound to block the interaction between CXCR4 and envelope gly coproteins from T-tropic strains of HIV-1. (C) 2001 Elsevier Science Ltd. A ll rights reserved.