Discovery of Modified Amidate (ProTide) Prodrugs of Tenofovir with Enhanced Antiviral Properties

This
study describes the discovery of novel prodrugs bearing tyrosine
derivatives instead of the phenol moiety present in FDA-approved tenofovir
alafenamide fumarate (TAF). The synthesis was optimized to afford
diastereomeric mixtures of novel prodrugs in one pot (yields up to
86%), and the epimers were resolved using a chiral HPLC column into
fast-eluting and slow-eluting epimers. In human lymphocytes, the most
efficient tyrosine-based prodrug reached a single-digit picomolar
EC50 value against HIV-1 and nearly 300-fold higher selectivity
index (SI) compared to TAF. In human hepatocytes, the most efficient
prodrugs exhibited subnanomolar EC50 values for HBV and
up to 26-fold higher SI compared to TAF. Metabolic studies demonstrated
markedly higher cellular uptake of the prodrugs and substantially
higher levels of released tenofovir inside the cells compared to TAF.
These promising results provide a strong foundation for further evaluation
of the reported prodrugs and their potential utility in the development
of highly potent antivirals.