Designed Vehicles for Blood Brain Barrier Traversal

设计用于穿越血脑屏障的车辆

• 批准号: 10614470
• 负责人: DAVID BAKER
• 金额: $ 49.55万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614470
• 关键词: Affinity; Alzheimer' s Disease; Amines; Antibodies; Binding; Binding Proteins; Biodistribution; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System; Clinical; Clinical Trials; DNA biosynthesis; Diffusion; Directed Molecular Evolution; Drug Delivery Systems; Escherichia coli; Feedback; Future; Gene Pool; Goals; Hydrogen Bonding; Hydrophobicity; In Vitro; Knowledge; Label; Libraries; Measures; Mediating; Mission; Modeling; Molecular Sieve Chromatography; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Neurologic; Neurological outcome; Nucleocapsid; Nutrient; Oncogenes; Outcome; Parkinson Disease; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Property; Protein Engineering; Proteins; Public Health; Radiolabeled; Rodent; Route; Side; Signal Transduction; Specificity; Stroke; Structure; Surface; Synthetic Genes; System; TFRC gene; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; United States National Institutes of Health; Variant; Vertebral column; X-Ray Crystallography; Yeasts; barrier to care; blood-brain barrier crossing; blood-brain barrier penetration; blood-brain barrier permeabilization; brain cell; chemical property; chemical synthesis; delivery vehicle; design; design,build,test; disability; improved; improved outcome; in vivo; innovation; insight; nervous system disorder; novel drug class; nucleic acid-based therapeutics; passive transport; receptor; receptor binding; screening; success; tool

PROJECT SUMMARY Emerging peptide-, protein-, and nucleic acid-based therapeutics for the treatment of Alzheimer’s disease and other neurologic conditions are blocked from diffusing into the brain by the blood–brain barrier (BBB). The long-term goal of this project is to deliver large therapeutic cargo such as these into the brain using designed BBB-crossing drug-delivery vehicles. The ​overall objectives are to (i) leverage recent breakthroughs in computational peptide design to yield new knowledge about BBB permeability and (ii) to designed from scratch new proteins that ferry cargo into the brain by exploiting natural systems that the brain uses to receive nutrients and signals. The ​central hypothesis is that the systematic design of functional biomolecules will yield new insights and tools for improving the delivery of large biomolecule therapeutics into the brain. The ​specific aims are: 1) to systematically and rationally discover the physiochemical properties which confer BBB permeability to designed peptide macrocycles (a promising new class of therapeutics); 2) to computationally design small, hyperstable proteins which bind to receptors that naturally cycle between the blood- and brain-side of the BBB; and 3) to fuse the binding proteins generated in Aim 2 to various drug-binding/packaging proteins, thereby creating protein assemblies that ferry large therapeutics into the brain. This project is ​innovative because it proposes to resolve a long-standing barrier to the treatment of neurologic diseases (namely, the difficulty of delivering therapeutics into the brain) by designing from scratch new BBB-crossing drug delivery vehicles. The project is ​significant because it is expected to provide tools which will improve outcomes in a range of future clinical trials of therapeutics which require delivery into the brain.

项目总结 新出现的基于肽、蛋白质和核酸的疗法治疗阿尔茨海默病和 其他神经疾病被血脑屏障(BBB)阻止扩散到大脑。这个 该项目的长期目标是使用专门设计的药物将这些药物输送到大脑中 BBB越境运送毒品的车辆。​的总体目标是：(I)利用最近在 计算多肽设计产生关于血脑屏障通透性的新知识和(Ii)从头开始设计 一种新的蛋白质，通过利用大脑接受营养的自然系统将货物运送到大脑 和信号。​的中心假设是，功能生物分子的系统设计将产生新的 改善大生物分子疗法进入大脑的洞察力和工具。​的具体目标 1)系统、合理地发现导致血脑屏障通透性的物理化学性质 设计多肽大环(一种很有前途的新疗法)；2)通过计算设计小的、 与受体结合的超稳定蛋白，这些受体在血脑屏障的血液和大脑一侧之间自然循环； 以及3)将目标2中产生的结合蛋白与各种药物结合/包装蛋白融合，从而 创造蛋白质组件，将大量治疗药物输送到大脑中。这个项目是​的创新项目，因为它 建议解决神经系统疾病治疗的一个长期障碍(即， 将治疗药物输送到大脑)，从零开始设计新的跨越血脑屏障的药物输送工具。这个 该项目具有重要的​意义，因为它有望提供可在一系列未来改进结果的工具 需要注射到大脑中的疗法的临床试验。