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Antimicrob. Agents Chemother. doi:10.1128/AAC.00692-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Intracellular Metabolism and Persistence of the Anti-Human Immunodeficiency Virus Activity of 2', 3'-Didehydro-3'-Deoxy-4'- Ethynylthymidine, A Novel Thymidine Analog

Departments of Pharmacology, and Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA, Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan, and School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan

^* To whom correspondence should be addressed. Email: yccheng{at}yale.edu.

	Abstract

The therapeutic benefits of current antiretroviral therapy (ART) are limited by the evolution of drug resistant virus and long-term toxicity. Novel antiretroviral compounds with antiviral activity against drug resistant viruses are needed. 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a novel thymidine analog, has potent anti-HIV activity, maintains considerable activity against multidrug resistant HIV strains, and is less inhibitory to mitochondrial DNA synthesis in cell culture than its progenitor D4T. We investigated the intracellular metabolism and anti-HIV activity of 4'-Ed4T. The profile of 4'-Ed4T metabolites was qualitatively similar to that of AZT with the monophosphate metabolite as the major metabolite, in contrast to D4T with relatively poor formation of total metabolites. The first phosphorylation step for 4'-Ed4T in cells was more efficient than D4T but less than that of AZT. The amount of 4'-Ed4TTP was higher than that of AZTTP at 24 h in culture. There was a dose-dependent accumulation of 4'-Ed4TDP, and 4'-Ed4TTP on up-regulation of TMPK, and PGK expressions in Tet-On RKO cells, respectively. The anti-HIV activity of 4'-Ed4T in cells persisted even after 48 h of drug removal from culture in comparison with AZT, D4T, and nevirapine. The order of increasing persistence of anti-HIV activity of these compounds after drug removal was 4'-Ed4T >D4T > AZT >NVP. In conclusion, with the persistence of 4'-Ed4TTP, and persistent anti-HIV activity in cells we anticipate less frequent dosing and less patient compliance issues than that of D4T. 4'-Ed4T is a promising antiviral candidate for HIV-1 chemotherapy.

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