Single-Dose Oral Influenza Antiviral Prodrug Enabled by Cholesterol Conjugation.

Abstract

Current influenza therapy relies heavily on oseltamivir (OSV), an ethyl ester prodrug of oseltamivir carboxylate (OC) requiring twice-daily dosing for 5 days because of its short half-life and rapid clearance. We developed a cholesterol-conjugated OC prodrug that achieved dramatically prolonged systemic OC exposure compared with OSV. The conjugate exhibited single-dose efficacy against H1N1 and H3N2 influenza in mice after oral administration under both therapeutic and prophylactic regimens, conferring up to 100% survival. Mechanistic studies revealed high plasma protein binding of conjugate (up to 89% bound) and attenuated yet sustained hydrolytic release of OC in the liver as key drivers of their prolonged retention. This long-lasting oral activity of OC-Cholesterol conjugate makes it attractive for further development to overcome the frequent dosing limitations of OSV. The cholesterol conjugation approach should be useful for developing novel prodrugs with enhanced pharmaceutical properties.