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Journal of Virology, April 1999, p. 3309-3316, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Irreversible Inhibition of Human Immunodeficiency Virus Type 1 Integrase by Dicaffeoylquinic Acidsdagger

Kai Zhu,1 Mara L. Cordeiro,1 Jocelyn Atienza,1 W. Edward Robinson Jr.,2 and Samson A. Chow1,*

Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095,1 and Department of Pathology and Microbiology and Molecular Genetics, University of California, Irvine, California 926972

Received 15 October 1998/Accepted 13 January 1999

Human immunodeficiency virus type 1 (HIV-1) and other retroviruses require integration of a double-stranded DNA copy of the RNA genome into the host cell chromosome for productive infection. The viral enzyme, integrase, catalyzes the integration of retroviral DNA and represents an attractive target for developing antiretroviral agents. We identified several derivatives of dicaffeoylquinic acids (DCQAs) that inhibit HIV-1 replication in tissue culture and catalytic activities of HIV-1 integrase in vitro. The specific step at which DCQAs inhibit the integration in vitro and the mechanism of inhibition were examined in the present study. Titration experiments with different concentrations of HIV-1 integrase or DNA substrate found that the effect of DCQAs was exerted on the enzyme and not the DNA. In addition to HIV-1, DCQAs also inhibited the in vitro activities of MLV integrase and truncated variants of feline immunodeficiency virus integrase, suggesting that these compounds interacted with the central core domain of integrase. The inhibition on retroviral integrases was relatively specific, and DCQAs had no effect on several other DNA-modifying enzymes and phosphoryltransferases. Kinetic analysis and dialysis experiments showed that the inhibition of integrase by DCQAs was irreversible. The inhibition did not require the presence of a divalent cation and was unaffected by preassembling integrase onto viral DNA. The results suggest that the irreversible inhibition by DCQAs on integrase is directed toward conserved amino acid residues in the central core domain during catalysis.

* Corresponding author. Mailing address: Department of Molecular and Medical Pharmacology, UCLA School of Medicine, 23-133 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095. Phone: (310) 825-9600. Fax: (310) 825-6267. E-mail: schow{at}mednet.ucla.edu.

dagger This report is dedicated to the memory of Brian Reese and others who suffered from and died of AIDS.

Journal of Virology, April 1999, p. 3309-3316, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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