SBIR-STTR Award

The HBV X protein (HBx) represents an attractive target for drug discovery efforts as it plays a central role inactivating viral gene expression and promoting conditions that allow the cccDNA form of HBV to persist in thehepatocytes of chronically infected individuals. The objective of this Phase I SBIR feasibility study is to identifydrug-like compounds that selectively inhibit a key interaction between HBx and a host factor DDB1 (UVdamaged 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 of200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjectedto follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interestingof these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activityrelationships (SAR). The overall goal of this project is to discover one or more novel lead series which isdefined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against HBV andminimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that willadvance the program from Early Lead Optimization through to Candidate Selection. PROJECT NARRATIVE 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. Adult ; 21+ years old ; Adult Human ; adulthood ; Alanine Transaminase ; ALT1 ; Alanine Aminotransferase ; Alanine-2-Oxoglutarate Aminotransferase ; Glutamic-Alanine Transaminase ; Glutamic-Pyruvate Transaminase ; Glutamic-Pyruvic Transaminase ; Interferon-alpha ; (IFN) α ; (IFN)-α ; (IFN)α ; Alferon ; IFN Alpha ; IFN α ; IFN-α ; IFNa ; IFNα ; Interferon Alfa-n3 ; Interferon-α ; Leukocyte Interferon ; Lymphoblast Interferon ; Lymphoblastoid Interferon ; inhibitor/antagonist ; inhibitor ; Antibodies ; Antiviral Agents ; Antiviral Drugs ; Antivirals ; anti-viral agents ; anti-viral drugs ; anti-virals ; Automobile Driving ; driving ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Chromosomes ; viral DNA ; virus DNA ; DNA-Binding Proteins ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Feasibility Studies ; Gene Expression ; Viral Genes ; Goals ; Hepatitis ; Hepatitis B ; Hepatitis B Infection ; Viral Hepatitis B ; infection with HBV ; infection with hepatitis B virus ; serum hepatitis ; Hepatitis B Surface Antigens ; Au antigen ; Australia Antigen ; HBsAg ; HBsAg (hepatitis B surface antigen) ; hepatitis associated antigen ; Primary carcinoma of the liver cells ; Hepatocarcinoma ; Hepatocellular Carcinoma ; Hepatocellular cancer ; Hepatoma ; Liver Cells Carcinoma ; liver carcinoma ; Human ; Modern Man ; indexing ; Infection ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Libraries ; Liver ; hepatic body system ; hepatic organ system ; Liver Cirrhosis ; Hepatic Cirrhosis ; Liver diseases ; Hepatic Disorder ; hepatic disease ; hepatopathy ; liver disorder ; Luciferases ; Luciferase Immunologic ; Maintenance ; Persons ; Drug Kinetics ; Pharmacokinetics ; Play ; Publishing ; Risk ; Role ; social role ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Structure-Activity Relationship ; chemical structure function ; structure function relationship ; Technology ; Testing ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Vaccines ; Viral Regulatory Proteins ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Virus Inhibitors ; viral inhibitor ; Virus Replication ; viral multiplication ; viral replication ; virus multiplication ; Hepatitis B X-Protein ; HBV X protein ; HBxAg ; Hepatitis B Virus-X ; hepatitis B virus X antigen ; hepatitis B virus X protein ; transcriptional transactivator hbx ; ubiquitin-protein ligase ; E3 Ligase ; E3 Ubiquitin Ligase ; Ubiquitin Protein Ligase ; Ubiquitin-Protein Ligase Complexes ; Ubiquitin-Protein Ligase E3 ; extrachromosomal DNA ; improved ; Acute ; Chronic ; Phase ; Histologic ; Histologically ; Series ; Evaluation ; Hepatocyte ; Hepatic Cells ; Hepatic Parenchymal Cell ; Liver Cells ; Individual ; Vertical Disease Transmission ; Vertical Transmission ; mother to child transmission ; Disease Progression ; analog ; Funding ; Collaborations ; Reverse Transcriptase Inhibitors ; Integration Host Factors ; Host Factor ; Host Factor Protein ; Life ; programs ; Viread ; Tenofovir ; Investigation ; Immunes ; Immune ; Complex ; Oral ; System ; Viral ; chronic HBV infection ; chronic hepatitis B virus infection ; Chronic Hepatitis B ; Lytotoxicity ; cytotoxicity ; success ; chemical library ; small molecule libraries ; DNA Replication ; DNA Synthesis ; DNA biosynthesis ; Gene Inactivation ; transcriptional silencing ; Gene Silencing ; early childhood ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; novel ; Property ; response ; High Throughput Assay ; high throughput screening ; drug discovery ; entecavir ; Molecular Interaction ; Binding ; preventing ; prevent ; small molecule ; Dose ; Host Defense Mechanism ; Molecular Target ; Perinatal Exposure ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Ubiquitination ; Ubiquitilation ; Ubiquitinoylation ; ubiquination ; ubiquitin conjugation ; Development ; developmental ; Cirrhosis ; cirrhotic ; Pathway interactions ; pathway ; UV induced DNA damage ; UV damaged DNA ; UV irradiated DNA ; ultraviolet damaged DNA ; ultraviolet induced DNA damage ; ultraviolet irradiated DNA ; counterscreen ; candidate selection ; lead series ; Drug Targeting ; seroconversion ; Hepatitis B Virus ; HBV ; Homologous Serum Hepatitis Virus ; recruit ; lead optimization ;

The HBV X protein (HBx) represents an attractive target for drug discovery efforts as it plays a central role inactivating viral gene expression and promoting conditions that allow the cccDNA form of HBV to persist in thehepatocytes of chronically infected individuals. The objective of this Phase I SBIR feasibility study is to identifydrug-like compounds that selectively inhibit a key interaction between HBx and a host factor DDB1 (UVdamaged 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 of200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjectedto follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interestingof these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activityrelationships (SAR). The overall goal of this project is to discover one or more novel lead series which isdefined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against HBV andminimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that willadvance the program from Early Lead Optimization through to Candidate Selection.

Public Health Relevance Statement:
PROJECT NARRATIVE 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.

Project Terms:
<21+ years old><(IFN) α><(IFN)-α><(IFN)α>