WAI JS, EGBERTSON MS, PAYNE LS, FISHER TE, EMBREY MW, TRAN LO, MELAMED JY, LANGFORD HM, GUARE JP, ZHUANG L, GREY VE, VACCA JP, HOLLOWAY MK, NAYLOR-OLSEN AM, HAZUDA DJ, FELOCK PJ, WOLFE AL, STILLMOCK KA, SCHLEIF WA, GABRYELSKI LJ, YOUNG SD; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 220.

Merck Res. Lab., West Point, PA

BACKGROUND: HIV-1 integrase catalyzes insertion of proviral DNA into the genome of host cell. Recently, a pyrrole diketoacid was reported to be a selective inhibitor of strand transfer (Hazuda, D. J. et al. Sci., 2000, 287, 646-650). This compound effectively prevents proviral DNA integration and inhibits HIV-1 replication in cell culture. Here we describe the structure-activity relationships (SAR) of a series of diketoacids.METHODS: Chemical design and synthesis. Enzyme assays were performed with recombinant HIV-1 integrase (0.1 micro-M) preassembled on immobilized oligonucleotides. Inhibitors were added subsequent to assembly and washings. The antiviral activity of the inhibitor was tested with MT-4 human T-lymphoid cells/ HIV-1[IIIb] culture. Virus spread was assessed by HIV-1 p24 core antigen ELISA.RESULTS: Modification of a screening lead provided a series of potent 3-benzylphenyl diketoacid HIV-1 integrase inhibitors. The most active compounds inhibit replication of HIV-1 in cell culture at CIC[95] = 0.1 to 0.3 micro-M. The most potent inhibitors are only two fold less potent than the protease inhibitor indinavir (CIC[95] 0.05 micro-M) in the same assay. Cytotoxicity was not observed in cell culture at concentrations up to 50 micro-M. Conclusion: A series of potent 3-benzylphenyl diketoacid HIV-1 integrase inhibitors has been identified.KEYWORDS: HIV; Inhibitors; Integrase

Publication Types:

• Meeting Abstracts

Keywords:

• Antiviral Agents
• Catalysis
• DNA Replication
• HIV Integrase
• HIV Integrase Inhibitors
• HIV-1
• Humans
• Integrases
• Oligonucleotides
• Structure-Activity Relationship
• antagonists & inhibitors
• genetics
• virology

Other ID:

• GWAIDS0010642

UI: 102248140

From Meeting Abstracts