SBIR-STTR Award

The synthesis and characterization of novel prodrugs of the antiviral nucleosides acyclovir, penciclovir, and lamivudine are proposed with the purpose of identifying an agent with improved efficacy in the treatment of hepatitis B. The proposed prodrugs are designed to target the nucleosides selectively to the liver in their monophosphate form, and to enhance significantly the formation of the corresponding nucleoside triphosphates (NTP's), which are potent inhibitors of hepatitis B virus (HBV) polymerase. Enhanced hepatic NTP formation is likely to confer more rapid and complete suppression of HBV replication, and consequently to prevent the emergence of drug resistance, a major problem with current therapies. Studies are planned that will address (a) prodrug activation by a liver-specific enzyme (b) prodrug activation and phosphorylation in isolated hepatocytes and (c) prodrug pharmacokinetics and hepatic NTP generation in the rat. A key indicator for the success of the prodrug approach and its therapeutic potential is the temporal profile of hepatic NTP levels in vivo relative to parent nucleoside. A favorable profile will provide the impetus for additional studies envisaged for phase II of the proposal: the assessment of efficacy in animal models of HBV and the toxicological evaluations necessary to support clinical development. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

Public Health Relevance Statement:


Project Terms:
laboratory rat; antiviral agent; prodrug; drug screening /evaluation; drug design /synthesis /production; liver cell; hepatitis B; liver disorder chemotherapy; liver pharmacology; acyclovir; nucleoside triphosphate; tissue /cell culture; toxicology; lamivudine

The long-term objective of this application is to identify a potent, efficacious and safe drug for the treatment of hepatitis C virus (HCV) through the use of our proprietary HepDirect prodrug technology. It is estimated that >170 million people are infected with Hepatitis C virus worldwide. Despite recent improvements in HCV drug formulations, a large segment of the patient population is still under treated. In the first phase of our SBIR grant support we demonstrated the potential of HepDirect prodrugs in selectively delivering high levels of phosphorylated nucleoside analogues to the liver. The work led to the identification of a development candidate (HepDirect-adefovir), which recently completed its initial Phase I clinical study and is expected to begin Phase 1/2 in early 2003. We now propose to continue the exploration of the HepDirect technology and its applications to a large and structurally-diverse set of nucleosides, with the goal of identifying a potent and selective inhibitor of HCV replication. Most nucleosides designed to be specific inhibitors of viral replication as the nucleoside triphosphate (NTP) fail as a result of poor recognition by the nucleoside kinases responsible for converting the nucleoside to the NTP. The HepDirect technology overcomes this limitation and allows us to pursue nucleoside analogues that are easily overlooked or discarded by companies pursuing standard drug discovery approaches. The specific aims of this application include the synthesis of a large number of HepDirect prodrugs of diverse nucleoside analogues, the production of the corresponding NTP library via the biological conversion of the prodrugs in hepatocytes, and the screening of this library for the inhibition of HCV replication. To support the antiviral activity determinations, a key aim is the development of a cellular assay compatible with the prodrug technology as well as a novel human tissue based HCV replication model. Following the identification of a lead inhibitor, the HepDirect prodrug moiety is optimized for intracellular activation efficiency, oral bioavailability, pharmacokinetics, as well as liver targeting. The final aim is to complete the requisite studies to launch the compound identified into full development for the treatment of HCV including second species pharmacokinetics, pilot animal toxicology, pilot in vitro and in vivo genetic toxicology and general safety pharmacology.

Public Health Relevance Statement:


Project Terms:
laboratory rat; antiviral agent; pharmacokinetics; prodrug; drug screening /evaluation; drug design /synthesis /production; western blotting; liver cell; hepatitis B; liver disorder chemotherapy; liver pharmacology; nucleoside analog; nucleoside monophosphate; nucleoside triphosphate; high performance liquid chromatography; virus replication; hepatitis C virus; hepatitis C; clinical research; drug discovery /isolation; liquid chromatography mass spectrometry