Single-Dose Oral Influenza Antiviral Prodrug Enabled by Cholesterol Conjugation

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.