CAREER: Sequence Defined Peptoid Materials for Selective Biodegradation

职业：用于选择性生物降解的序列定义的类肽材料

• 批准号: 2046746
• 负责人: Adrianne Rosales
• 金额: $ 55.95万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2046746&HistoricalAwards=false
• 关键词: CAREER; Sequence; Defined; Peptoid; Materials

Non-Technical SummaryThe cells in the human body produce many types of molecules that degrade materials in their environment. These molecules can be small and non-specific, such as highly reactive radicals, or they can be large and more targeted, such as enzymes. The ability to sense which degradative molecules are present through simple bench top assays would enable more efficient characterization of disease states such as cancer or inflammation. This project will therefore study the degradation behavior of peptoids, a class of synthetic molecules that offers the potential to degrade selectively one type of biomolecule (radical species) but not another (enzymes). This selectivity will enable the design of peptoid-based sensors to non-invasively identify which degradative molecules are present in a biological environment, and this knowledge will also impact the design of new materials with well-defined degradation properties for use in biomedical implants. The proposed project will also include educational and outreach activities at the high school, undergraduate, and graduate student level to broaden the participation of diverse groups in biomaterials research. Specifically, it will develop a mentoring program to facilitate interactions among students from underrepresented populations in STEM at the annual Texas Biomaterials Day. Technical Summary Reactive oxygen/nitrogen species (ROS/RNS) and matrix metalloproteases (MMPs) are critical drivers of extracellular matrix remodeling, especially during disease and inflammation. Degradable peptides and proteins are commonly exploited as ROS and MMP sensors; however, a key challenge is cross-reactivity and limited selectivity toward one type of degradative species. Non-natural peptoids (or N-substituted glycines) offer an attractive platform with which to address these limitations due to their proteolytically-stable N-substituted polyamide backbone and potential selective susceptibility to ROS/RNS. In addition, peptoids preserve the monomer sequence definition of biomolecules but utilize an expanded class of side chain functionalities, which may access higher specificity to MMP degradation in hybrid substrates. The proposed research activities will combine synthesis with mass spectrometry and new degradation assays to: 1) define the selectivity and sensitivity of non-natural peptoids toward biologically relevant oxidative mechanisms of degradation, 2) determine monomer sequence effects on the specificity of hybrid substrate degradation by MMPs, and 3) assess peptoid-based biomaterials as platforms to simultaneously detect mixtures of ROS and MMPs. These studies will lead to fundamental insights regarding peptoid degradation behavior in complex biological environments and enable the development of peptoid-based sensors and materials for applications in tissue engineering, disease modeling, and diagnostic screening. In addition, the proposed educational activities will establish a new mentoring program to enhance the participation of students from Minority Serving Institutions and Historically Black Colleges and Universities in Texas at the annual Texas Biomaterials Day. Best practices from this mentoring program will be shared via webinar to facilitate the broad implementation of similar programs at the nine other Biomaterials Days across the country.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术概述人体细胞产生多种类型的分子，这些分子能在其环境中降解物质。这些分子可以是小的、非特异性的，比如高活性的自由基，也可以是大的、更有针对性的，比如酶。通过简单的桌面分析来感知存在哪些降解分子的能力，将使人们能够更有效地表征癌症或炎症等疾病状态。因此，该项目将研究类肽的降解行为，这是一类合成分子，可以选择性地降解一种类型的生物分子(自由基物种)，但不能降解另一种生物分子(酶)。这种选择性将使基于肽类的传感器的设计能够非侵入性地识别生物环境中存在的降解分子，这一知识也将影响用于生物医学植入物的具有明确降解特性的新材料的设计。拟议的项目还将包括高中、本科生和研究生层面的教育和推广活动，以扩大不同群体对生物材料研究的参与。具体地说，它将制定一个指导计划，以促进来自STEM代表不足群体的学生在一年一度的德克萨斯生物材料日上的互动。技术概述活性氧/氮(ROS/RNS)和基质金属蛋白酶(MMPs)是细胞外基质重塑的关键驱动因素，尤其是在疾病和炎症过程中。可降解的多肽和蛋白质通常被用作ROS和MMPs的传感器；然而，一个关键的挑战是对一种类型的降解物种的交叉反应和有限的选择性。非天然类肽(或N-取代甘氨酸)由于其蛋白质水解性稳定的N-取代聚酰胺骨架和潜在的对ROS/RNS的选择性敏感性而提供了一个有吸引力的平台来解决这些限制。此外，类肽保留了生物分子的单体序列定义，但利用了一类扩展的侧链功能，这可能对杂交底物中的基质金属蛋白酶的降解具有更高的特异性。拟议的研究活动将结合合成、质谱学和新的降解分析方法：1)确定非天然类肽对生物相关氧化降解机制的选择性和敏感性，2)确定单体序列对MMPs杂化底物降解特异性的影响，以及3)评估基于类肽的生物材料作为同时检测ROS和MMPs混合物的平台。这些研究将导致对复杂生物环境中的类肽降解行为的基本见解，并使基于类肽的传感器和材料的开发应用于组织工程、疾病建模和诊断筛查。此外，拟议的教育活动将建立一个新的指导计划，以加强来自少数族裔服务机构和德克萨斯州历史上的黑人学院和大学的学生在一年一度的德克萨斯州生物材料日的参与。该指导计划的最佳实践将通过网络研讨会分享，以促进类似计划在全国其他九个生物材料日的广泛实施。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Fluorescent Peptomer Substrates for Differential Degradation by Metalloproteases

• DOI: 10.1021/acs.biomac.2c01077
• 发表时间: 2022-10-21
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Austin，Mariah J.;Schunk，Hattie;Rosales，Adrianne M.
• 通讯作者: Rosales，Adrianne M.

Peptomer substrates for quantitative pattern-recognition sensing of proteases

• DOI: 10.1039/d2cc06587h
• 发表时间: 2023-01-17
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Austin，Mariah J. J.;Schunk，Hattie C. C.;Rosales，Adrianne M. M.
• 通讯作者: Rosales，Adrianne M. M.

Oxidative degradation of sequence-defined peptoid oligomers

序列定义的类肽寡聚体的氧化降解

• DOI: 10.1039/d2me00179a
• 发表时间: 2023
• 期刊: Molecular Systems Design & Engineering
• 影响因子: 3.6
• 作者: Schunk, Hattie C.;Austin, Mariah J.;Taha, Bradley Z.;McClellan, Matthew S.;Suggs, Laura J.;Rosales, Adrianne M.
• 通讯作者: Rosales, Adrianne M.