Rational optimization of a HIV-1 Tat inhibitor: rapid progress on combinatorial lead structures.
Lead molecules identified by combinatorial chemistry approaches are preferred starting points for straightforward improvements of compound profiles. Structure-guided rationales can be supported and complemented by systematic variations based on the modular nature of the molecules. A peptoidic compound (CGP 64222), previously identified from a sequential unrandomization process, was shown to specifically inhibit the interaction between the HIV-1 trans-activator Tat and its RNA response element TAR. To improve the compound's pharmaceutical attractiveness an approach to reduce both, size and number of charges was pursued. Because this resulted in activity decrease, parallel synthesis with variations on one rationally defined position aimed at the identification of structural determinants was undertaken to regain in vitro 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 human cells.
Institute for Medical Microbiology, University of Basel, Basel, Switzerland.
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D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D001667:Binding, Competitive; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes; D013058:Mass Spectrometry; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D034444:Peptoids; D015533:Transcriptional Activation / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D000166:Acridines; D019380:Anti-HIV Agents; C120265:CGP 74026; D015696:Gene Products, tat; D009842:Oligopeptides; D034444:Peptoids; D054322:tat Gene Products, Human Immunodeficiency Virus