Both herpes simplex virus type 1 (HSV-1) and HSV-2 encode a
thymidine kinase enzyme which differs from cellular
thymidine kinase in substrate specificity. Viral
thymidine kinase enables the virus to replicate in cells that lack cellular
thymidine kinase, namely those of the sensory neurons where the virus establishes, and periodically reactivates from, a latent state.
Thymidine kinase-dependent HSV replication following viral reactivation at the site of latency is thought to precede the emergence of virus at mucosal surfaces. The ability to inhibit such an essential viral
enzyme would potentially prevent HSV from replicating within neuronal tissue, and thus stop the recurrent disease cycle.
Ro 32-2313 was designed as a selective and competitive inhibitor of HSV
thymidine kinase and in vitro studies have confirmed this mechanism of action. In vivo evaluation of a soluble
prodrug of
Ro 32-2313,
Ro 32-4397, was undertaken in murine models where pathogenesis was dependent upon viral replication in neuronal tissue. It was shown that in vivo administration of
Ro 32-4397 (i) significantly reduced the viral titre detected in isolated dorsal root ganglia; (ii) prevented HSV-2-induced lethality in a systemic
infection model; and (iii) reduced zosteriform lesion development in a model of dermal
infection. Administration of
Ro 32-4397 produced dose-related changes in viral pathogenicity towards those of the phenotype of a
thymidine kinase-deficient virus. Overall, the study confirmed that
thymidine kinase inhibitors can suppress the replication of HSV in vivo, and suggest that such inhibitors may reduce reactivation of the virus from latency if used prophylactically in recurrent HSV
infection.