Rational optimization of a HIV-1 Tat inhibitor: Rapid progress on combinatorial lead structures

Lead molecules identified by combinatorial chemistry approaches are preferr ed starting points for straightforward improvements of compound profiles. S tructure-guided rationales can be supported and complemented by systematic variations based on the modular nature of the molecules. A peptoidic compou nd (CGP 64222), previously identified from a sequential unrandomization pro cess, was shown to specifically inhibit the interaction between the HIV-1 t rans-activator Tat and its RNA response element TAR. To improve the compoun d's pharmaceutical attractiveness an approach to reduce both, size and numb er of charges was pursued. Because this resulted in activity decrease, para llel synthesis with variations on one rationally defined position aimed at the identification of structural determinants was undertaken to regain in v itro activity in biochemical and cellular Tat-TAR interaction assays. As a result CGP74026 was identified, a drastically simplified but highly active Tat antagonist, which is able to block HIV-1 replication even in primary hu man cells. (C) 1999 John Wiley & Sons, Inc.