In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 49, No. 12 ( 2005-12), p. 4965-4973
Kurzfassung:
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 (IC 50 ) than those of cidofovir (CDV) and ganciclovir (GCV) (IC 50 , 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 IC 50 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.
Materialart:
Online-Ressource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.49.12.4965-4973.2005
Sprache:
Englisch
Verlag:
American Society for Microbiology
Publikationsdatum:
2005
ZDB Id:
1496156-8
SSG:
12
SSG:
15,3
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