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

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

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

Biotechnol Bioeng. 1998-99;61(3):155-68. Unique Identifier : AIDSLINE MED/99328735
Klimkait T; Felder ER; Albrecht G; Hamy F; Institute for Medical Microbiology, University of Basel, Basel,; Switzerland.

Abstract: 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. Copyright 1999 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 61:155-168, 1998/1999.

Keywords: JOURNAL ARTICLE Acridines/*CHEMICAL SYNTHESIS/PHARMACOLOGY Anti-HIV Agents/*CHEMICAL SYNTHESIS Binding, Competitive Gene Products, tat/*ANTAGONISTS & INHIB Hela Cells Human HIV Long Terminal Repeat/GENETICS HIV-1/DRUG EFFECTS Lymphocytes Molecular Structure Oligopeptides/*CHEMICAL SYNTHESIS/PHARMACOLOGY Spectrum Analysis, Mass Trans-Activation (Genetics)/DRUG EFFECTS
991030
A99A0951

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