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.
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