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Antimicrobial Agents and Chemotherapy, December 2005, p. 4965-4973, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4965-4973.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus

Weimin Zhu,^1, Angela Burnette,^1, Dorjbal Dorjsuren,^1, Paula E. Roberts,^1, Mahmoud Huleihel,² Robert H. Shoemaker,³ Victor E. Marquez,⁴ Riad Agbaria,⁵ and Shizuko Sei^1*

Laboratory of Antiviral Drug Mechanisms, SAIC-Frederick, Frederick, Maryland,¹ National Institute for Biotechnology and Department of Virology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel,² Screening Technologies Branch, Developmental Therapeutics Program, NCI-Frederick, Frederick, Maryland,³ Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, Frederick, Maryland,⁴ Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel⁵

Received 26 April 2005/ Returned for modification 31 July 2005/ Accepted 19 September 2005

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS). Blocking lytic KSHV replication may hinder KS tumorigenesis. Here, we report potent in vitro anti-KSHV activity of 2'-exo-methanocarbathymidine [North-methanocarbathymidine (N-MCT)], a thymidine analog with a pseudosugar ring locked in the northern conformation, which has previously been shown to block the replication of herpes simplex virus types 1 and 2. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC₅₀) than those of cidofovir (CDV) and ganciclovir (GCV) (IC₅₀, mean ± standard deviation: 0.08 ± 0.03, 0.42 ± 0.07, and 0.96 ± 0.49 µM for N-MCT, CDV, and GCV, respectively). The reduction in KSHV virion production was accompanied by a corresponding decrease in KSHV DNA levels in the N-MCT-treated BCBL-1 cells, indicating that the compound blocked lytic KSHV DNA replication. A time- and dose-dependent accumulation of N-MCT-triphosphate (TP) was demonstrated in lytically induced BCBL-1 cells, while uninfected cells showed virtually no accumulation. The levels of N-MCT-TP were significantly decreased in the presence of 5'-ethynylthymidine, a potent inhibitor of herpesvirus thymidine kinase, resulting in the abrogation of anti-KSHV activity of N-MCT. N-MCT-TP more effectively blocked in vitro DNA synthesis by KSHV DNA polymerase with an IC₅₀ of 6.24 ± 0.08 µM (mean ± standard deviation) compared to CDV-diphosphate (14.70 ±2.47 µM) or GCV-TP (24.59 ± 5.60 µM). Taken together, N-MCT is a highly potent and target-specific anti-KSHV agent which inhibits lytic KSHV DNA synthesis through its triphosphate metabolite produced in KSHV-infected cells expressing a virally encoded thymidine kinase.

Present address: Laboratory of Human Toxicology & Pharmacology, Developmental Therapeutics Program, SAIC/NCI-Frederick, Frederick, Md.

Present address: SuperArray Bioscience Corporation, Frederick, Md.

Present address: Southern Research Institute, Frederick, Md.

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