Inhibition of human immunodeficiency virus integrase by bis-catechols.
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.
LaFemina
R L
RL
Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Graham
P L
PL
LeGrow
K
K
Hastings
J C
JC
Wolfe
A
A
Young
S D
SD
Emini
E A
EA
Hazuda
D J
DJ
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
D002396:Catechols; D004254:DNA Nucleotidyltransferases; D019426:Integrases