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Small molecule inhibitors of HBx that decrease hepatitis B virus replication

减少乙型肝炎病毒复制的 HBx 小分子抑制剂

基本信息

批准号：
10284389
负责人：
Sue Ellen Crawford
金额：
$ 24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284389
关键词：
Affinity Animal Model Antiviral Agents Antiviral Therapy Apoptosis Area Bar Codes Binding Biological Biological Assay Biological Process Cancer Etiology Categories Cause of Death Cell Cycle Progression Cell Nucleus Cell physiology Chromosomal Stability Chronic Chronic Hepatitis B Circular DNA Cirrhosis Clinical Clinical Trials Collaborations Computer software DNA DNA Sequence DNA sequencing Development Drug Kinetics Drug Targeting Drug usage Epitopes Future Genetic Transcription Goals HBV Genotype Hepatitis B Hepatitis B Core Antigen Hepatitis B Surface Antigens Hepatitis B Virus Hepatocyte Human Infection Interferon-alpha Knowledge Lead Libraries Life Life Cycle Stages Liver Cirrhosis Liver Stem Cell Luciferases Maintenance Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Medicine Messenger RNA Methods Modeling Natural Immunity Nuclear Organoids Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Primary carcinoma of the liver cells Production Proteins Proteolysis Regulation Reverse Transcriptase Inhibitors Risk Role Signal Transduction Structure-Activity Relationship Technology Testing Therapeutic Time Toxic effect Viral Viral Proteins Virus Virus Diseases Virus Replication analog base chronic infection clinically relevant college cost drug discovery drug metabolism drug resistant virus entecavir first-in-human genetic regulatory protein in vivo evaluation innovation multicatalytic endopeptidase complex multidisciplinary mutant novel novel strategies novel therapeutics pre-clinical prevent protein degradation recruit side effect small molecule small molecule inhibitor virus related cancer

项目摘要

Chronic infection with hepatitis B virus (HBV) is the 7th leading cause of death worldwide and the 5th leading cause of cancer. The key to HBV chronic infection is the nuclear localized HBV episomal covalently closed circular DNA (cccDNA) that drives HBV transcription and replication. The risk of HCC is directly related to the level of replication from the cccDNA. An HBV cure requires eliminating cccDNA, which is not feasible at present. However, achieving a functional cure, defined as a sustained loss of hepatitis B surface antigen (HBsAg), may be possible by silencing the cccDNA. The current therapies, treatment with interferon alpha or life-long maintenance on nucleos(t)ide analogs, have low functional cure rates highlighting the critical need for new HBV therapeutics. The HBV HBx protein is an excellent candidate for the development of antivirals due to its critical roles in the virus life cycle – regulation of viral transcription, degradation of viral restriction factors that silence cccDNA, and interference with many host cellular processes. Despite its central role, HBx has yet to be the target of antiviral therapy. Our central hypothesis is that targeting HBx will inhibit viral replication, silence cccDNA, and facilitate an HBV functional cure. Our proposed studies build on several recent advances. First, we have shown HBx interacts with cellular DDB1 to mediate the degradation of cellular proteins known to silence cccDNA. Second, we have developed an authentic HBV infection model using human liver stem cell-derived organoids (HLOs). Finally, we have established a collaboration with the Center for Drug Discovery (CDD) at Baylor College of Medicine that has developed 50 libraries containing over 5 billion novel DNA-bar coded small drug-like molecules (DEC-Tec). We now propose a highly innovative project to ultimately identify new HBV antivirals that target HBx. In Aim 1, purified HBx protein will be screened by affinity selection against the DEC- Tec libraries. Binders will be identified by DNA sequencing and validated with fresh target protein. Considering that HBx interacts with over 100 cellular proteins, we expect to identify multiple HBx binders. Structure-activity relationship (SAR) will be determined using computational software, and the binder's affinity for HBx measured. Compounds with SAR and high affinity will be pursued. In Aim 2, high affinity HBx binders will be screened for the ability to inhibit the critical HBx-DDB1 interaction as measured in a split luciferase assay. Compounds that inhibit HBx-DDB1 will then be tested for the ability to inhibit HBV replication in the HLO replication model and compared against the known nucleos(t)ide analogue entecavir. Successful HBx binders will serve as leads for future in vivo evaluation that includes toxicity, drug metabolism, and pharmacokinetics. Other high affinity binders can be incorporated into proteolysis targeting chimeric molecules (PROTACs) for proteasome-mediated degradation. Worldwide, over 257 million people are chronically infected with HBV and approximately 1 million die each year of liver cirrhosis or cancer. The proposed studies hold tremendous potential for the discovery of novel approaches to treat chronic HBV, prevent HBV-associated cancer, and lead to a functional cure.

慢性乙型肝炎病毒（HBV）感染是全球第七大死因，也是第五大死因