Pharmacophore identification of a specific CXCR4 inhibitor, T140, leads todevelopment of effective anti-HIV agents with very high selectivity indexes

A polyphemusin peptide analogue, T22 ([Tyr(5,12), Lys(7)]-polyphemusin II), and its shortened potent analogues, T134 (des[Cys(8,13), Tyr(9,12)]-[D-Lys (10), Pro(11), L-citrulline(16)]-T22 without C-terminal amide) and T140 {[L -3-(2-naphthyl)alanine(3)]-T134}, strongly inhibit the T-cell line-tropic ( T-tropic) HIV-1 infection through their specific binding to a chemokine rec eptor, CXCR4. T22 is an extremely basic peptide possessing five Arg and thr ee Lys residues in the molecule. In our previous study, we found that there is an apparent correlation in the T22-related peptides between the number of total positive charges and anti-HIV activity or cytotoxicity. Here, we h ave conducted the conventional Ala-scanning study in order to define the an ti-HIV activity pharmacophore of T140 (the strongest analogue among our com pounds) and identified four indispensable amino acid residues (Arg(2), Nal( 3), Tyr(5), and Arg(14)). Based on this result, a series of L-citrulline (C it)-substituted analogues of T140 with decreased net positive charges have been synthesized and evaluated in terms of anti-HIV activity and cytotoxici ty. As a result, novel effective inhibitors, TCl4003 and TCl4005, possessin g higher selectivity indexes (SIs, 50% cytotoxic concentration/50% effectiv e concentration) than that of T140 have been developed. (C) 2000 Elsevier S cience Ltd. All rights reserved.