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. 2006 Apr;50(4):1336-41.
doi: 10.1128/AAC.50.4.1336-1341.2006.

Activity and mechanism of action of N-methanocarbathymidine against herpesvirus and orthopoxvirus infections

Mark N Prichard  1 , Kathy A Keith, Debra C Quenelle, Earl R Kern
Affiliations

Activity and mechanism of action of N-methanocarbathymidine against herpesvirus and orthopoxvirus infections

Mark N Prichard et al. Antimicrob Agents Chemother. 2006 Apr.

Abstract

N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (N)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.

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Figures

FIG. 1.
FIG. 1.
Structure of (N)-MCT.
FIG. 2.
FIG. 2.
Inhibition of VV DNA synthesis by (N)-MCT. Monolayers of HFF cells were infected with the WR strain of VV and incubated with increasing concentrations of the drugs as illustrated in the figure (0.03, 0.1, 3, 10, and 30 μg/ml). Purified DNA was cut with EcoRV, and a 3,259-bp fragment of VV DNA was detected with a digoxigenin-labeled DNA probe. Numbers at left are molecular sizes in base pairs. CC and VC designate cell control and virus control, respectively.
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