Carbonyl J Derivatives: A New Class of HIV-1 Integrase Inhibitors

✍ Scribed by Karl Maurer; Ann H. Tang; George L. Kenyon; Andrew D. Leavitt

• Publisher: Elsevier Science
• Year: 2000
• Tongue: English
• Weight: 207 KB
• Volume: 28
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1006/bioo.2000.1166

✦ Synopsis

Integration of a DNA copy of the HIV-1 genome is required for viral replication and pathogenicity, and this highly specific molecular process is mediated by the virus-encoded integrase protein. The requirement for integration, combined with the lack of a known analogous process in mammalian cells, makes integrase an attractive target for therapeutic inhibitors of HIV-1 replication. While many reports of HIV-1 IN inhibitors exist, no such compounds have yet emerged to treat HIV-1 infection. As such, new classes of integrase inhibitors are needed. We have combined molecular modeling and combinatorial chemistry to identify and develop a new class of HIV-1 integrase inhibitors, the Carbonyl J [N,N'-bis(2-(5-hydroxy-7-naphthalenesulfonic acid)urea] derivatives. This new class includes a number of compounds with sub-micromolar IC(50) values for inhibiting purified HIV-1 integrase in vitro. Herein we describe the chemical characteristics that are important for integrase inhibition and cell toxicity within the Carbonyl J derivatives. Copyright 2000 Academic Press.