Discovery of novel anti-HBV compounds targeting host factors

发现针对宿主因子的新型抗乙肝病毒化合物

• 批准号: 8731770
• 负责人: Alan McLachlan
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731770
• 关键词: Adherence; Anabolism; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Factors; Biology; Carrier State; Cell Culture Techniques; Cells; Chemicals; Chicago; Chronic; Chronic Hepatitis B; Clinic; Communities; Complement; Computer Assisted; Consensus; Development; Drug Design; Drug Kinetics; Drug Targeting; Evaluation; Generations; Genetic Transcription; Goals; Hepatitis B Virus; Illinois; Integration Host Factors; Interferons; Lead; Libraries; Life; Life Cycle Stages; Mass Spectrum Analysis; Mediating; Methods; Molecular; Molecular Models; Molecular Weight; Nuclear Receptors; Nucleocapsid; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Photoaffinity Labels; Prevention; Probability; RNA chemical synthesis; RNA-Directed DNA Polymerase; Records; Research; Research Personnel; Resolution; Techniques; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Universities; Vial device; Viral; Virus Diseases; Work; analog; animal efficacy; anti-hepatitis B; assay development; base; cellular targeting; design; efficacy evaluation; experience; hepatitis B virus P protein; high throughput screening; inhibitor/antagonist; molecular modeling; novel; novel strategies; novel therapeutics; nucleoside analog; promoter; public health relevance; research study; scaffold; screening; small molecule; small molecule libraries; therapy development; Adherence; Anabolism; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Factors; Biology; Carrier State; Cell Culture Techniques; Cells; Chemicals; Chicago; Chronic; Chronic Hepatitis B; Clinic; Communities; Complement; Computer Assisted; Consensus; Development; Drug Design; Drug Kinetics; Drug Targeting; Evaluation; Generations; Genetic Transcription; Goals; Hepatitis B Virus; Illinois; Integration Host Factors; Interferons; Lead; Libraries; Life; Life Cycle Stages; Mass Spectrum Analysis; Mediating; Methods; Molecular; Molecular Models; Molecular Weight; Nuclear Receptors; Nucleocapsid; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Photoaffinity Labels; Prevention; Probability; RNA chemical synthesis; RNA-Directed DNA Polymerase; Records; Research; Research Personnel; Resolution; Techniques; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Universities; Vial device; Viral; Virus Diseases; Work; analog; animal efficacy; anti-hepatitis B; assay development; base; cellular targeting; design; efficacy evaluation; experience; hepatitis B virus P protein; high throughput screening; inhibitor/antagonist; molecular modeling; novel; novel strategies; novel therapeutics; nucleoside analog; promoter; public health relevance; research study; scaffold; screening; small molecule; small molecule libraries; therapy development

DESCRIPTION (provided by applicant): This R21 exploratory proposal uses an integrated approach to discover lead candidates suitable for further lead optimization as therapeutics for chronic hepatitis B virus (HBV) infections. Our long-term objective is to develop small molecule inhibitors of HBV biosynthesis with a novel mechanism of action distinct from the currently available drugs. A broad consensus exists in the HBV research community that the key to the successful development of new novel classes of HBV medications lies in targeting steps in the viral life cycle other than replication mediated by the HBV polymerase/reverse transcriptase. Currently available medications, including type 1 interferon and nucleosides analogs, do not offer a significant probability for the resolution of the chronic carrier state. The shortcomings o the existing HBV therapeutic regiments include the necessity of life-long treatment and suboptimal patient acceptance and adherence. Clearly, new drugs with novel mechanisms of action are needed to find a cure leading to complete eradication of HBV infection. Antiviral therapy development targeting not viral, but cellular components essential for viral biosynthesis may represent a novel approach for the generation of HBV therapeutics. A combination of nucleoside analogs with the novel drugs targeting host factors may potentially lead to the prevention of new cccDNA synthesis. Recent advances in target identification techniques for therapeutically relevant chemical compounds and the availability of simple assays amenable to HTS analysis for the evaluation of HBV transcription allow for a multitude of methods to discover new therapeutic agents for HBV. We hypothesize that it will be possible to identify and design inhibitors of HBV biosynthesis by specifically targeting cellular factors that are essential for vial pregenomic RNA synthesis using a combination of approaches: high- throughput screening (HTS) against HBV nucleocapsid promoter activity, computer-aided drug design (CADD), chemical biology, target identification methods, target-oriented rational drug design, medicinal chemistry, and evaluation for efficacy of the most promising compounds shown to inhibit HBV transcription and replication in cell culture. To achieve this goal, our specific aims are as follo: Aim 1. Identify lead- or drug-like low molecular weight inhibitors of HBV nucleocapsid promoter activity using high- throughput screening of chemical libraries with available primary HTS, counter-screening HTS, and secondary viral replication assays. Aim 2. Design and synthesize analogs of the most promising HBV antiviral compounds from aim 1 to generate a SAR and identify compounds suitable for cell-based and photoaffinity-based target identification experiments. If time permits, pilot target identification studies using non-hepatoma cells complemented with a panel of nuclear receptors capable of supporting HBV transcription and replication, and photoaffinity labeling followed by LC-MS/MS analysis will be performed.

描述（由申请人提供）：该R21探索性建议使用一种集成的方法来发现适合进一步铅优化的铅候选者，作为慢性乙型肝炎病毒（HBV）感染的治疗剂。我们的长期目标是开发HBV生物合成的小分子抑制剂，具有与当前可用药物不同的新作用机理。 HBV研究社区中存在广泛的共识，即成功开发新型HBV药物的关键在于针对病毒生命周期的步骤，而不是由HBV聚合酶/逆转录酶介导的复制。当前可用的药物，包括1型干扰素和核苷类似物，对慢性载体状态的分辨率没有很大的可能性。现有的HBV治疗团的缺点包括终身治疗的必要性以及次优的患者接受和依从性。显然，需要具有新型作用机理的新药来找到一种治疗，从而完全消除了HBV感染。抗病毒疗法的发育靶向不是病毒，而是病毒生物合成必不可少的细胞成分可能代表了HBV疗法产生的新方法。核苷类似物与靶向宿主因子的新药物的结合可能会导致预防新的CCCDNA合成。对于治疗相关化合物的目标识别技术的最新进展以及可用于评估HBV转录的HTS分析的简单测定的可用性，可以采用多种方法来发现HBV的新治疗剂。 We hypothesize that it will be possible to identify and design inhibitors of HBV biosynthesis by specifically targeting cellular factors that are essential for vial pregenomic RNA synthesis using a combination of approaches: high- throughput screening (HTS) against HBV nucleocapsid promoter activity, computer-aided drug design (CADD), chemical biology, target identification methods, target-oriented rational drug design, medicinal化学和评估对抑制细胞培养中HBV转录和复制的最有希望化合物的功效。为了实现这一目标，我们的具体目标是作为Follo：AIM 1。使用具有可用的原发性HTS，反筛查HTS和二级病毒复制评估的化学文库的高吞吐量筛选，确定HBV Nucleocapsid启动子的铅或类似药物的低分子量抑制剂。 AIM 2。设计和合成来自AIM 1的最有希望的HBV抗病毒化合物的类似物，以生成SAR并识别适合基于细胞和基于光的基于光的目标识别实验的化合物。如果时间允许，则使用非肝瘤细胞的试验靶标识别研究，这些细胞与能够支持HBV转录和复制的一组核受体，以及光性标记，然后进行LC-MS/MS分析。