Zanamivir–Cholesterol Conjugate: A Long-Acting Neuraminidase Inhibitor with Potent Efficacy against Drug-Resistant Influenza Viruses

Antiviral
therapy of influenza virus infections depends heavily
on two viral neuraminidase (NA) inhibitors, oseltamivir (OSV) and
zanamivir (ZNV). The efficacy of OSV is challenged by the development
of viral resistance, while the clinical use of ZNV is limited by its
poor pharmacokinetic profile and requirement for twice-daily intranasal
administration. We have developed a novel NA inhibitor by conjugating
ZNV to cholesterol. The ZNV−cholesterol conjugate showed markedly
improved antiviral efficacy and plasma half-life compared with ZNV.
Single-dose administration of the conjugate protected the mice from
lethal challenges with wild-type or mutant H1N1 influenza viruses
bearing an OSV-resistant H275Y-substitution. Mechanistic studies showed
that the conjugate targeted the cell membrane and entered the host
cells, thereby inhibiting the NA function and the assembly of progeny
virions. The ZNV–cholesterol conjugate represents a potential
new treatment for influenza infections with sustained effect. Cholesterol
conjugation may be an effective strategy for improving the pharmacokinetics
and efficacy of other small-molecule therapeutics.