More than 350 million people are chronically infected by Hepatitis B Virus (HBV) and are at high risk for developing cirrhosis and liver cancer. Current drugs do not cure HBV and do not target covalently closed- circular DNA (cccDNA), which has been linked to viral persistence in HBV-infected hepatocytes. Moreover, current therapies require lifetime treatment to suppress viral load and prolonged treatments lead to the development of drug resistant strains. Finally, there is only a single family of directly acting antiretrovirals (DAAs) that can block HBV infection, preventing meaningful combination therapies equivalent to formidable highly active antiretroviral therapies (HAART) that tipped the scales in the fight against AIDS. The long term goal of this work is to develop HBV therapies that lead to HBV eradication. It is hypothesized that combinations of novel, potent, and selective inhibitors of HBV can lead to more efficient suppression of reverse transcription (RT), lack of cross-resistance, synergistic mechanism of action and depletion of cccDNA, which in turn could lead to the eradication of HBV. Towards that end, this project focuses on the development of leads that target viral replication by capsid assembly effectors (CAEs) and highly potent novel NRTIs. The following specific aims are proposed:
Specific Aim 1 : Characterize the potency determinants of novel highly active NRTIs.
Specific Aim 2 : Discovery and characterization of novel capsid assembly effectors (CAEs) Specific Aim 3: Characterization of novel NRTI and CAE combinations These studies will identify promising leads for the development of future anti-HBV drugs from two different classes and will help design novel combinations that should efficiently suppress cccDNA by targeting Cp and include highly potent HBV NRTIs towards a sustained virological response that could lead to HBV eradication.
This project aims to identify promising leads for the development of anti-HBV drugs which target multiple functions of the virus life cycle. These studies should help design new therapeutic combinations that could lead to better treatments for HBV-infected individuals and eventually to eradication of HBV infection.
| Huber, Andrew D; Wolf, Jennifer J; Liu, Dandan et al. (2018) The Heteroaryldihydropyrimidine Bay 38-7690 Induces Hepatitis B Virus Core Protein Aggregates Associated with Promyelocytic Leukemia Nuclear Bodies in Infected Cells. mSphere 3: |
| Tang, Jing; Huber, Andrew D; Pineda, Dallas L et al. (2018) 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors. Eur J Med Chem 164:179-192 |
| Markowitz, Martin; Sarafianos, Stefan G (2018) 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS 13:294-299 |
| Huber, Andrew D; Michailidis, Eleftherios; Tang, Jing et al. (2017) 3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H. Antimicrob Agents Chemother 61: |
