Exploration of naturally occurring chemical structures for medicinal uses has received significant interest in
drug discovery and development research in the past few decades. None have had more success or products of greater clinical efficacy than synthetic analogs of
nucleosides and
nucleotides, especially as
antiviral drugs. Nucleos(t)ide
antivirals are synthetic analogs of the natural building blocks of
DNA or
RNA. This review focuses on the developmental path of
tenofovir disoproxil fumarate (TDF), a
prodrug of a
nucleotide analog and its clinical applications as a first-line
antiviral for
chronic hepatitis B (CHB).
Tenofovir is a potent
antiviral compound, but has poor oral availability. The disoproxil
fumarate (DF)
prodrug moiety greatly enhances intestinal absorption allowing it to become an oral medication.
Tenofovir is activated intracellularly, and the incorporation into HBV
DNA prevents further elongation thus terminating replication. In patients with CHB, TDF has demonstrated broad, potent and sustained virologic response. Maintenance of viral suppression for up to 5 years resulted in regression of
fibrosis and
cirrhosis. No
tenofovir-resistant HBV variants have been detected in patients after long-term use. The efficacy and safety profiles reported from cohort studies of clinical practices were consistent with those observed in registration trials. Continuous development includes a new oral
prodrug,
tenofovir alafenamide fumarate (TAF), which has enhanced delivery of
tenofovir to target cells compared to TDF.