Discovery of next-generation dengue NS4B inhibitors

下一代登革热 NS4B 抑制剂的发现

• 批准号: 10514156
• 负责人: Christopher Sarko
• 金额: $ 238.48万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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/10514156
• 关键词: ADME Study; Antiviral Agents; Antiviral Therapy; Autophagocytosis; Binding; Biochemical; Blood; Blood Cells; Canis familiaris; Cardiovascular system; Cells; Clinical Management; Clinical Trials; Combined Modality Therapy; Complex; Country; Culicidae; Deforestation; Dengue; Dengue Virus; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Ensure; Funding; Generations; Goals; Hepatotoxicity; Human; Incidence; Infection; Integral Membrane Protein; Interferons; International; Joints; Knowledge; Lead; Membrane Proteins; Methods; Mus; Neuraxis; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phototoxicity; Plasma; Play; Property; Proteins; Proteomics; Rattus; Recovery; Reporting; Research; Resistance; Resistance profile; Risk; Rodent; Safety; Serotyping; Signal Transduction; Supportive care; Therapeutic; Toxicology; Translational Research; Travel; Validation; Viral; Virus; Virus Diseases; Virus Replication; attributable mortality; base; carbonate dehydratase; climate change; clinical candidate; clinical development; clinical translation; drug candidate; drug discovery; druggable target; experience; fitness; genotoxicity; improved; inhibitor; inhibitor therapy; mosquito-borne; next generation; novel; pandemic preparedness; pre-clinical; preclinical development; resistance mechanism; respiratory; safety study; tool; virology

PROJECT 5 – ABSTRACT The goal of this project is to discover next-generation dengue NS4B inhibitors. We currently have a pan-dengue serotype NS4B inhibitor NITD-688 in phase I clinical trial. Preclinical results suggest two potential liabilities that might threaten this compound for further development. Thus, we will develop a second-generation compound to mitigate the liabilities. We will achieve the goal by pursuing three aims. (i) Optimize the next generation of dengue NS4B inhibitor. We have developed a comprehensive medicinal chemistry optimization strategy to improve the compound properties. (ii) Conduct preclinical characterization and deliver an IND-ready next-generation NS4B inhibitor. (iii) Determine the mode-of-action and resistance potential of NITD-688. NS4B is a transmembrane protein that participates in replication complex through interacting with other viral and host proteins. We will take chemo-proteomic, biochemical, and cellular approaches to define the mechanism of compound inhibition. Such knowledge can be applied to other membrane proteins for antiviral discovery.

项目5--摘要 该项目的目标是发现下一代登革热NS4B抑制剂。我们目前有一起泛登革热 血清型NS4B抑制剂NITD-688正在进行I期临床试验。临床前研究结果表明有两种潜在的风险 可能会威胁到这种化合物的进一步发展。因此，我们将开发一种第二代化合物来 减轻债务。我们将通过追求三个目标来实现这一目标。(一)优化下一代登革热 NS4B抑制剂。我们制定了全面的药物化学优化策略，以提高 复合属性。(Ii)进行临床前鉴定并提供可供IND使用的下一代NS4B 抑制剂。(3)测定NITD-688的作用模式和抗性电位。NS4B是一种跨膜蛋白 通过与其他病毒和宿主蛋白相互作用而参与复制复合体的蛋白质。我们会带上 用化学蛋白质组学、生化和细胞学的方法来确定化合物抑制的机制。是这样的 这些知识可以应用于其他膜蛋白，用于抗病毒的发现。