Light-Actuatable NanoRobots for Molecular Uncaging

用于分子解禁的光驱动纳米机器人

• 批准号: 8356212
• 负责人: Xue Han
• 金额: $ 245.55万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356212
• 关键词: Active Sites; Adverse effects; Brain; Cells; DNA; Development; Drug Compounding; Hormones; In Vitro; Ligands; Light; Modification; Molecular; Nervous system structure; Neuromodulator; Neurosciences; Neurotransmitters; Organ; Organism; Peptides; Pharmacologic Substance; Proteins; Resolution; System; Time; Ultraviolet Rays; Visible Radiation; abstracting; biological systems; body system; caged molecule; chemical group; complex biological systems; design; frontier; in vivo; irradiation; millisecond; nanorobot; novel strategies; operation; public health relevance; small molecule; spatiotemporal; success

DESCRIPTION (Provided by the applicant) Abstract: Precise spatiotemporal control of ligand delivery into intact cells, organs, and organisms is important for the time resolved and causal analysis of the functions of neurotransmitters, neuromodulators, and hormones in the operation of complex biological systems, such as the brain. Over the past several decades, some success has been achieved in uncaging several small molecules through the attachment of photolabile chemical groups, which block the bioactivity of the molecule in the absence of light and release a bioactive molecule upon UV light irradiation. However, such photochemical uncaging modifications are difficult to develop for small molecules, and are nearly impossible for large molecules whose active sites are often too large to be blocked by the addition of chemical groups. In addition, caged molecules often exert leak bioactivity even before light delivery, and the use of UV light can be damaging to cellular components; as a result, despite proven utility in vitro, uncaging has been little used in vivo to study intact biological systems. Here, I will describe a novel strategy capable of uncaging arbitrary bioactive molecules and peptides with millisecond time scale resolution, using visible light safe for in vivo use. I will use computational protein and DNA design to construct light controllable 'NanoRobots', and use these NanoRobots to uncage a variety of molecules, peptides, and proteins in the intact organ systems. Such a strategy has the potential to revolutionize the study of ligand functions with unprecedented spatiotemporal precision, opening up new frontiers in basic molecular and systems neuroscience, pharmaceutical development, and side effect assessment. Public Health Relevance: The ability to deliver compounds and drugs with high spatiotemporal precision will drastically advance our understanding of the functions of neurotransmitters and neuromodulators in the nervous system. Here, I describe a novel strategy capable of delivering arbitrary bioactive molecules, peptides with millisecond time resolution, using a light controllabl NanoRobot.

描述（由申请人提供） 摘要：精确的时空控制的配体输送到完整的细胞，器官和生物体是重要的时间分辨和因果分析的功能的神经递质，神经调质和激素在复杂的生物系统，如大脑的操作。在过去的几十年中，通过连接对光不稳定的化学基团，在解开几种小分子方面取得了一些成功，这些化学基团在没有光的情况下阻断分子的生物活性，并在UV光照射时释放生物活性分子。然而，这样的光化学解开修饰对于小分子是难以开发的，并且对于其活性位点通常太大而不能通过添加化学基团来阻断的大分子几乎是不可能的。此外，笼状分子甚至在光递送之前经常发挥泄漏生物活性，并且使用UV光可能对细胞组分造成损害;因此，尽管在体外证明了实用性，但在体内很少使用解开来研究完整的生物系统。在这里，我将描述一种新颖的策略， 能够以毫秒级时间尺度分辨率，使用对体内使用安全的可见光来解开任意生物活性分子和肽。我将使用计算蛋白质和DNA设计来构建光可控的“纳米机器人”，并使用这些纳米机器人在完整的器官系统中释放各种分子，肽和蛋白质。这种策略有可能以前所未有的时空精度彻底改变配体功能的研究，开辟基础分子和系统神经科学，药物开发和副作用评估的新前沿。 公共卫生相关性：以高时空精度递送化合物和药物的能力将极大地推进我们对神经系统中神经递质和神经调质功能的理解。在这里，我描述了一种新的策略，能够提供任意的生物活性分子，肽与毫秒级的时间分辨率，使用光可移动的纳米机器人。