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Antimicrobial Agents and Chemotherapy, January 1998, p. 140-146, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Brenda McDougall,1 Peter J. King,2 Bor Wen Wu,3 Zdenek Hostomsky,3 Manfred G. Reinecke,4 and W. Edward Robinson Jr.1,2,*

Departments of Pathology1 and Microbiology and Molecular Genetics,2 University of California, Irvine, California 92697-4800; Research Laboratories, Agouron Pharmaceuticals, Inc., San Diego, California 921213; and Department of Chemistry, Texas Christian University, Fort Worth, Texas 761294

Received 26 June 1997/Returned for modification 27 August 1997/Accepted 5 November 1997

Current pharmacological agents for human immunodeficiency virus (HIV) infection include drugs targeted against HIV reverse transcriptase and HIV protease. An understudied therapeutic target is HIV integrase, an essential enzyme that mediates integration of the HIV genome into the host chromosome. The dicaffeoylquinic acids (DCQAs) and the dicaffeoyltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their specificity against HIV integrase in cell culture has been questioned. Thus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-1 reverse transcriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibited HIV replication at concentrations between 2 and 12 µM. Their activity against reverse transcriptase ranged from 7 µM to greater than 100 µM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 µM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 µM. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, they were found to have no activity. Therefore, the DCQAs and DCTAs exhibit >10- to >100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their observed anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs are a potentially important class of HIV inhibitors that act at a site distinct from that of current HIV therapeutic agents.

* Corresponding author. Mailing address: Department of Pathology, D440 Med Sci I, University of California, Irvine, CA 92697-4800. Phone: (714) 824-3431. Fax: (714) 824-2505. E-mail: ewrobins{at}uci.edu.

Antimicrobial Agents and Chemotherapy, January 1998, p. 140-146, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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