A Proof-of-Concept Study for the Efficacy of Dispirotripiperazine PDSTP in a Mouse Model of Herpes Simplex Herpetic Encephalitis.

Herpes simplex encephalitis (HSE) remains a life-threatening disease with high mortality and severe neurological complications, despite acyclovir therapy being limited by delayed diagnosis, drug resistance, and poor blood-brain barrier penetration. New antivirals with different mechanisms of action are urgently needed. We evaluated PDSTP, a novel dispirotripiperazine-based compound targeting host heparan sulfate proteoglycans (HSPGs), in mouse models of HSV-1 encephalitis. This study evaluates the therapeutic and prophylactic potential of PDSTP, an antiviral compound that blocks HSV glycoconjugates on the host cell membrane, using a well-established mouse model of herpes encephalitis. BALB/c mice were infected with HSV-1 strains VR-539 or VR-733 via intraperitoneal (IP) or intranasal (IN) routes. PDSTP was administered orally (PO) or intraperitoneally (IP) at 12.5-80 mg/kg/day, alone or in combination with acyclovir (10-100 mg/kg/day), using a prophylactic-therapeutic regimen (2 h pre-infection, then twice daily for 7 days). Survival, weight loss, mean survival time, and brain viral loads were assessed. PDSTP at 80 mg/kg/day (PO) protected 30-40% of VR-733-infected mice and extended lifespan 1.9-fold (p < 0.05), comparable to acyclovir at 100 mg/kg/day. IP administration was superior to PO. The combination of IP PDSTP (12.5 mg/kg/day) with IP acyclovir (10 mg/kg/day) achieved 100% survival, prevented weight loss, and significantly reduced brain viral titers (p < 0.001) in both infection models. PDSTP demonstrates dose- and strain-dependent activity as monotherapy and enhanced efficacy when combined with acyclovir. The IP combination provided complete protection at low doses, supporting PDSTP as a promising candidate for further development against HSE.