title: Inhibition of human immunodeficiency virus integrase by bis-catechols.
abstract: The human immunodeficiency virus type 1 (HIV-1) integrase protein is required for the productive infection of T-lymphoid cells in culture (R. L. LaFemina, C. L. Schneider, H. L. Robbins, P. L. Callahan, K. LeGrow, E. Roth, W. A. Schleif, and E. A. Emini, J. Virol. 66:7414-7419, 1992). This observation suggests that chemical inhibitors of integrase may prevent the spread of HIV in infected individuals. In our search for such potential chemotherapeutic agents, we observed that beta-conidendrol inhibits both the sequence-dependent and sequence-independent endonucleolytic activities of integrase with comparable potencies in vitro (50% inhibitory concentration, 500 nM). Structurally related compounds tested for their abilities to inhibit integrase generated a limited structure-activity analysis which demonstrated that potency is associated with the bis-catechol structure: two pairs of adjacent hydroxyls on separate benzene rings. beta-Conidendrol did not inhibit several other endonucleases and/or phosphoryltransferases. Although beta-conidendrol was not effective in preventing HIV-1 infection in cell culture, the in vitro data demonstrate that it is possible to identify selective agents targeted against this essential HIV-1 function.
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: LaFemina
authors.forename: P L
authors.initials: PL
authors.lastname: Graham
authors.forename: K
authors.initials: K
authors.lastname: LeGrow
authors.forename: J C
authors.initials: JC
authors.lastname: Hastings
authors.forename: A
authors.initials: A
authors.lastname: Wolfe
authors.forename: S D
authors.initials: SD
authors.lastname: Young
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: D J
authors.initials: DJ
authors.lastname: Hazuda
mesh_terms: D001483:Base Sequence; D002396:Catechols / Q000494:pharmacology*; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000201:enzymology*; D019426:Integrases; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D002396:Catechols; D004254:DNA Nucleotidyltransferases; D019426:Integrases