Structural determinants of nervous system exposure of adibelivir (IM-250) and related herpes helicase-primase inhibitors across animal species.

The high incidence and prevalence of herpes infections pose a significant health burden worldwide. Herpes simplex virus infections are the cause of herpes labialis, genital herpes or herpes keratitis and in rare cases life-threatening herpes encephalitis, meningitis or disseminated disease. After primary infection, herpes simplex viruses (HSVes) establish latency in the trigeminal and sacral ganglia and at least 30 % of patients experience clinically manifestant recurrences for life. For effective treatment of these neurotrophic HSVes, adequate drug exposure in the nervous system is essential. Here we report the post administration exposure of structurally different helicase-primase inhibitors (HPIs) in plasma, blood, organs and, in particular, the nervous system of animals by HPLC/MS. In diverse animal species, after single or multiple doses of helicase-primase drugs by oral or intravenous administration, only adibelivir (IM-250) achieved concentrations in the nervous system in the range of plasma or blood levels (ratio 0.5 to 4 nervous system/plasma), while other helicase-primase inhibitors with distinct structures, including amenamevir, pritelivir or ABI-5366, showed a low brain/plasma ratio of less than 0.1. The efficient passage of helicase-primase drugs through the blood-brain and blood-nerve barrier is based on their distinct structure and chemical properties. In preclinical studies published so far, adibelivir was efficacious in the herpes encephalitis and neonatal animal model and reduced the reactivation competence of the neuronal latent herpes viral reservoir. Ongoing clinical trials with HPIs will show whether sufficient drug exposure in brain and ganglia will translate into more effective herpes therapies for patients.