The HBV X protein (HBx) represents an attractive target for drug discovery efforts as it plays a central role in activating viral gene expression and promoting conditions that allow the cccDNA form of HBV to persist in the hepatocytes of chronically infected individuals. The objective of this Phase I SBIR feasibility study is to identify drug-like compounds that selectively inhibit a key interaction between HBx and a host factor DDB1 (UV damaged DNA binding protein 1) that is responsible for activating transcription from the cccDNA template. During the course of this Phase I funding period, we will execute a hit finding campaign against a library of 200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against HBV and minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.
Despite the availability of a safe and effective vaccine, there remains over 257 million people chronically infected with hepatitis B virus (HBV) world-wide. Current therapies are not curative and only slow disease progression. New strategies are, therefore, needed to further suppress viral replication and provide the conditions that are required for immune control of viral replication known as a ?functional cure?. Here, we propose high throughput screening of a 200,000 compound small-molecule library with a novel assay to identify inhibitors of HBx, a key viral regulatory protein that is essential for HBV replication and persistence.
