PHARMACOPHORE IDENTIFICATION OF A CHEMOKINE RECEPTOR (CXCR4) ANTAGONIST, T22 ([TYR(5,12), LYS(7)]-POLYPHEMUSIN-II), WHICH SPECIFICALLY BLOCKS T-CELL-LINE-TROPIC HIV-1 INFECTION

We have previously found that T22 ([Tyr(5,12), Lys(7)]-polyphemusin II ) has strong anti-human immunodeficiency virus (HIV) activity, and tha t T22 inhibits T cell-lint-tropic HIV-1 infection mediated by CXCR4/fu sin. T22 is an 18-residue peptide amide, which takes an antiparallel b eta-sheet structure that is maintained by two disulfide bridges. Struc ture-activity relationship (SAR) studies on T22 have disclosed the con tributions of each region of T22 to activity or cytotoxicity, and have provided the following useful information to develop new CXCR4 antago nists: The number of Arg residues in the N-terminal and C-terminal reg ions of T22 is closely related to anti-HIV activity. Addition of a var iety of functional groups at the N-terminal end results in increases i n activity. Disulfide rings, especially the major disulfide loop, are indispensable for anti-HIV activity and maintenance of the beta-sheet structure. Trp(3) can be replaced by other aromatic residues (Tyr, Phe and L-2-naphthylalanine). Between two repeats of Tyr-Arg-Lys, which a re a characteristic structure in T22, Tyr-Arg-Lys in the N-terminal po rtion is more closely associated with anti-HIV activity and maintenanc e of the beta-sheet structure. A positive charge in the side chain at the (i + 1) position of the beta-turn region is necessary for strong a ctivity. Through these studies, we have found several compounds having higher selectivity indexes (50% cytotoxic concentration/50% effective concentration) than that of T22, (C) 1998 Elsevier Science Ltd. All r ights reserved.