Advances in Nucleoside Monophosphate Prodrugs as Anti-HCV Agents

The document from 2010 reviews the development of nucleoside monophosphate (NMP) prodrugs as potential treatments for Hepatitis C virus (HCV), which affects about 3% of the global population. It discusses the limitations of current treatments and the challenges in delivering sufficient concentrations of anti-HCV nucleoside triphosphate (NTP) analogues to the HCV polymerase. Various prodrug strategies, such as ProTides, S-acyl-2-thioethyl (SATE) MP prodrugs, and HepDirect prodrugs, are explored for their potential to improve intracellular NTP levels and target specific organs. The document reports on studies that have shown promising in vitro and in vivo results, including a Phase I trial with IDX-184 involving 41 patients that demonstrated a mean viral load decrease after 3 days. However, issues such as intracellular delivery of toxic agents, low yields in preparation, and potential toxicity are highlighted as challenges that need to be addressed. The document concludes that while these prodrugs have shown promising activity, their utility in clinical applications, particularly for liver-directed treatments, remains to be determined.