Development of direct-acting flavivirus inhibitors

直接作用黄病毒抑制剂的开发

• 批准号: 10513687
• 负责人: Ralph S Baric
• 金额: $ 395.75万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513687
• 关键词: Amino Acids; Antiviral Agents; Arthropods; Authorization documentation; Binding; Biochemical; Biodistribution; Biological Assay; Biology; Cells; Chemicals; Chemistry; Clinical Trials; Collaborations; DNA; Dengue Virus; Development; Disease; Disease Outbreaks; Docking; Dose; Drug Industry; Drug Kinetics; Environment; Enzymatic Biochemistry; Enzymes; Evolution; Excretory function; Exhibits; Family; Fever; Flaviviridae; Flavivirus; Flavivirus Infections; Formulation; Future; Goals; Health; Human; In Vitro; Infection; Investigational New Drug Application; Japanese encephalitis virus; Laboratories; Lead; Medical; Metabolism; Modeling; Mutagenesis; Nonstructural Protein; Nucleosides; Pathology; Peptide Hydrolases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pregnancy loss; Pregnant Women; Process; Protein Engineering; RNA Polymerase Inhibitor; RNA Viruses; RNA-Directed RNA Polymerase; Reporter; Resistance; Role; Series; Serology; Site; South America; Structure-Activity Relationship; Symptoms; Technology; Testing; Tick-Borne Encephalitis Virus; Toxic effect; Undifferentiated; Validation; Viral; Viral Load result; Virus; Virus Replication; West Nile virus; Yellow fever virus; Zika Virus; absorption; analog; anti-viral efficacy; antiviral drug development; base; cell type; clinical development; commercialization; drug development; enzyme activity; fetal; global health; helicase; high throughput screening; human disease; in vivo; inhibitor; innovation; interest; lead candidate; lead optimization; malformation; mouse model; novel; pandemic disease; prevent; response; reverse genetics; small molecule; small molecule libraries; structural biology; viral fitness; virtual

ABSTRACT Development of potent and broad-spectrum direct acting antivirals (DAAs) is key as a first-line defense against diseases caused by flaviviruses (e.g., dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, Zika virus and tick-borne encephalitis virus). To promote global health, the underlying premise of this proposal is to combine expertise and cutting-edge technology of academic and pharmaceutical sectors to establish a robust environment for drug identification and commercialization. The envisioned development process of broad-spectrum DAAs against flaviviruses is divided in three stages (aim 1–3). The first aim entails the identification and validation of conserved flavivirus targets and hits (driven by Discovery Core B and the Enzymology Core C. Already identified RNA-dependent RNA polymerase (RdRp) hits will serve as the chemical starting point for further optimization by MedChem Core D. In addition, in collaboration with the Discovery Core B, we aim to identify novel structurally conserved binding pockets of the following key viral replication enzymes: nonstructural protein 5 (NS5) RdRp, NS3 helicase, and NS2B-NS3 protease. Compounds targeting those sites will be explored using virtual docking, targeted small-molecule and fragment-based high- throughput screens and DNA-encoded chemical library (DEL) screens. Target sites will be validated in enzymatic assays. We will determine the role of key amino acids in enzyme activity, viral replication and fitness through protein engineering. At least two to four hit series will then be optimized and tested in aim 2 (Hit to Lead). Compounds will be characterized for activity in biochemical and cell-based viral replication assays, for favorable in vitro drug absorption, distribution, metabolism, excretion and toxicity (ADME-TOX), mechanism of action and resistance. Our heterogeneous flavivirus panel will assess the level of broad-spectrum antiviral activity in diverse cell types. While we aim to develop broad-spectrum anti-flavivirus drugs, several flaviviruses cause significant human disease globally, so highly selective inhibitors will also be pursued as appropriate. Lead compounds will be shared with Projects 1, 2, 3, and 5 to evaluate breadth across other viral families. At least two lead compounds selected in aim 2 will be tested in aim 3 for in vivo efficacy. After proof of concept in an in vivo study, we anticipate to deliver one Flavivirus inhibitor active against at least one flavivirus, or at best against all flaviviruses described in this proposal, ready to start Investigational New Drug Application (IND)/ Clinical Trial Authorization (CTA)-enabling studies, and subsequently if approved, enter clinical development and start Phase1 studies.

摘要 开发高效、广谱的直接作用抗病毒药物(DAA)是一线防御的关键 预防由黄病毒引起的疾病(例如登革热病毒、黄热病病毒、西尼罗河病毒、日本 脑炎病毒、寨卡病毒和森林脑炎病毒)。为了促进全球健康，潜在的 这一建议的前提是将学术和技术的专业知识和前沿技术相结合 制药部门为药品识别和商业化创造良好的环境。这个 设想的广谱抗黄病毒DAA的发展过程分为三个阶段(目的 1-3)。第一个目标是识别和确认保守的黄病毒靶标和命中。 (由Discovery Core B和Enzymology Core C推动)已经确定了依赖RNA的RNA 聚合酶(RdRp)HITS将作为MedChem Core进一步优化的化学起点 D.此外，与探索核心B合作，我们的目标是识别新的结构保守的 以下关键病毒复制酶的结合口袋：非结构蛋白5(NS5)RdRp，NS3 解旋酶和NS2B-NS3蛋白酶。针对这些位置的化合物将使用虚拟对接进行探索， 靶向小分子和基于片段的高通量筛选和DNA编码的化学库 (戴尔)屏幕。靶点将在酶分析中进行验证。我们将确定关键氨基的作用 通过蛋白质工程，酸在酶活性、病毒复制和健身中的作用。至少有两到四次命中 然后系列将在目标2(从点击到领先)中进行优化和测试。化合物的特征将是 在生化和基于细胞的病毒复制分析中的活性，以利于体外药物吸收， 分布、代谢、排泄和毒性(ADME-TOX)、作用机制和耐药性。我们的 异质性黄病毒小组将评估不同细胞类型中广谱抗病毒活性的水平。 虽然我们的目标是开发广谱抗黄病毒药物，但几种黄病毒对人类 因此，还将酌情寻求具有高度选择性的抑制剂。先导化合物将是 与项目1、2、3和5共享，以评估其他病毒家族的广度。至少领先两个 在目标2中选择的化合物将在目标3中进行体内疗效测试。在In中进行概念验证之后 体内研究，我们预计提供一种对至少一种黄病毒有效的黄病毒抑制剂，或者最多 对抗本建议书中描述的所有黄病毒，准备开始研究新药申请(IND)/ 临床试验授权(CTA)-启用研究，如果获得批准，随后进入临床开发 并开始第一阶段的研究。