CAREER: Molecular Engineering of Bio-orthogonal Stabilized Alpha Helices

职业：生物正交稳定α螺旋的分子工程

• 批准号: 1553860
• 负责人: Greg Thurber
• 金额: $ 50万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1553860&HistoricalAwards=false
• 关键词: CAREER; Molecular; Engineering; Bio; orthogonal

1553860 Thurber, Greg Novel molecular engineering strategies are rapidly enabling the development of unique bio-inspired molecules for materials, separations, drug, and medical imaging agent applications. However, these natural molecules often degrade at the conditions necessary for their use, such as in acidic or basic pH solutions when purifying a product or in the body where enzymes degrade the compounds before they can reach their therapeutic target. By using synthetic organic molecules to stabilize these biological materials, the agents can be engineered with both vast complexity and high stability. Furthermore, by choosing an appropriate chemical technique, high-throughput methods can be developed to rapidly select useful molecules from libraries of millions of compounds. This work will support basic research into the fundamental properties of these semi-synthetic materials and enable applied research to develop novel compounds for diverse applications. This CAREER proposal will combine novel synthetic linkers, non-natural amino acid (NNAA) incorporation, and bio-orthogonal chemistry with directed evolution to engineer stabilized helices with unique targeting properties. Aim 1 of this proposal will characterize a novel series of azide-alkyne stabilized alpha helices that possess unique chemical, imaging, and pharmacokinetic properties and are compatible with cell surface directed evolution. This arrangement only requires one type of NNAA in the peptide backbone to reduce complexity and increase overall incorporation efficiency. The longer linker can be engineered with a functional handle for attachment to beads, fluorescent dyes, radiolabels, or pharmacokinetic modifiers. This modular design enables these molecules to be used in multiple applications including separations, intracellular targeting, and imaging. Aim 2 of the proposal will capitalize on the bio-orthogonal chemistry to select novel helices. A site-specific linkage is introduced to select for molecules that will retain binding while attached to the linker. This proposal will alleviate the current development bottleneck by screening millions of novel stabilized helices for new therapeutics, imaging agents, and separations components. Engineering functionally diverse stabilized peptide and protein structures will impact several fields including the chemical industry, biomedical engineering field, pharmaceutical industry, and medical community. To grow the pipeline of highly qualified and diverse engineering students to fulfill these jobs, a science-focused outreach program will be created for students from local under-resourced schools in the Detroit area. Multiple interactions with students from predominantly under-represented backgrounds facilitate hands-on activities directly related to molecular engineering research. These students will visit the University of Michigan for interactive sessions to enhance their scientific understanding and encourage them to pursue science, technology, engineering, and mathematics (STEM) fields.This CAREER award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Systems and Synthetic Biology Program of the Division of Molecular and Cellular Biosciences.

小行星1553860 新的分子工程策略正在迅速开发独特的生物启发分子，用于材料，分离，药物和医学成像剂应用。然而，这些天然分子通常在其使用所需的条件下降解，例如在纯化产品时在酸性或碱性pH溶液中或在体内酶降解化合物才能到达其治疗靶点。通过使用合成的有机分子来稳定这些生物材料，这些试剂可以被设计成具有巨大的复杂性和高稳定性。此外，通过选择适当的化学技术，可以开发高通量方法，从数百万化合物的库中快速选择有用的分子。这项工作将支持对这些半合成材料基本特性的基础研究，并使应用研究能够开发出适用于不同应用的新型化合物。该CAREER提案将结合联合收割机新型合成接头、非天然氨基酸（NNAA）掺入和生物正交化学与定向进化，以设计具有独特靶向特性的稳定螺旋。本提案的目的1将表征一系列新的叠氮化物-炔稳定的α螺旋，其具有独特的化学、成像和药代动力学性质，并且与细胞表面定向进化相容。这种排列在肽骨架中仅需要一种类型的NNAA，以降低复杂性并提高总体掺入效率。较长的接头可以用功能性手柄工程化，用于连接到珠、荧光染料、放射性标记或药代动力学修饰剂。这种模块化设计使这些分子能够用于多种应用，包括分离、细胞内靶向和成像。该提案的目标2将利用生物正交化学来选择新的螺旋。引入位点特异性连接以选择在连接至接头时将保持结合的分子。这一建议将缓解目前的发展瓶颈，筛选数以百万计的新的稳定的螺旋新的治疗，显像剂，和分离组件。 工程化功能多样的稳定肽和蛋白质结构将影响多个领域，包括化学工业、生物医学工程领域、制药工业和医学界。为了培养高素质和多样化的工程专业学生来完成这些工作，将为底特律地区当地资源不足的学校的学生创建一个以科学为重点的外展计划。与来自主要代表性不足的背景的学生的多次互动促进了与分子工程研究直接相关的实践活动。这些学生将参观密歇根大学的互动会议，以提高他们的科学理解，并鼓励他们追求科学，技术，工程和数学（STEM）领域。这个CAREER奖由CBET部门的生物技术和生物化学工程项目共同资助，由分子和细胞生物科学部门的系统和合成生物学项目共同资助。