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Antimicrobial Agents and Chemotherapy, March 1998, p. 487-494, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of Acute-, Latent-, and Chronic-Phase Human Immunodeficiency Virus Type 1 (HIV-1) Replication by a Bistriazoloacridone Analog That Selectively Inhibits HIV-1 Transcription

Jim A. Turpin,1 Robert W. Buckheit Jr.,2 David Derse,3 Melinda Hollingshead,4 Karen Williamson,1 Carla Palamone,1 M. Clayton Osterling,2 Shawn A. Hill,3 Lisa Graham,1 Catherine A. Schaeffer,1 Ming Bu,1 Mingjun Huang,1 Wieslaw M. Cholody,5 Christopher J. Michejda,5 and William G. Rice1,*

Laboratory of Antiviral Drug Mechanisms, Developmental Therapeutics Program, SAIC Frederick,1 Laboratory of Leukocyte Biology, Division of Basic Sciences,3 Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment, Diagnosis and Centers,4 and Molecular Aspects of Drug Design, Macromolecular Structure Laboratory, ABL-Basic Research Program,5 National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, and Virology Research Group, Southern Research Institute-Frederick Research Center, Frederick, Maryland 217012

Received 7 August 1997/Returned for modification 20 October 1997/Accepted 11 December 1997

Nanomolar concentrations of temacrazine (1,4-bis[3-(6-oxo-6H-v-triazolo[4,5,1-de]acridin-5-yl)amino-propyl]piperazine) were discovered to inhibit acute human immunodeficiency virus type 1 (HIV-1) infections and suppress the production of virus from chronically and latently infected cells containing integrated proviral DNA. This bistriazoloacridone derivative exerted its mechanism of antiviral action through selective inhibition of HIV-1 transcription during the postintegrative phase of virus replication. Mechanistic studies revealed that temacrazine blocked HIV-1 RNA formation without interference with the transcription of cellular genes or with events associated with the HIV-1 Tat and Rev regulatory proteins. Although temacrazine inhibited the in vitro 3' processing and strand transfer activities of HIV-1 integrase, with a 50% inhibitory concentration of approximately 50 nM, no evidence of an inhibitory effect on the intracellular integration of proviral DNA into the cellular genome during the early phase of infection could be detected. Furthermore, temacrazine did not interfere with virus attachment or fusion to host cells or the enzymatic activities of HIV-1 reverse transcriptase or protease, and the compound was not directly virucidal. Demonstration of in vivo anti-HIV-1 activity by temacrazine identifies bistriazoloacridones as a new class of pharmaceuticals that selectively blocks HIV-1 transcription.

* Corresponding author. Mailing address: Laboratory of Antiviral Drug Mechanisms, Developmental Therapeutics Program, National Cancer Institute-Frederick Cancer Research and Development Center, SAIC Frederick, Building 431T-B, P.O. Box B, Frederick, MD 21702-1201. Phone: (301) 846-5060. Fax: (301) 846-6846. E-mail: rice{at}dtpax2.ncifcrf.gov.

Antimicrobial Agents and Chemotherapy, March 1998, p. 487-494, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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