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Synthesis, assembly, and properties of dehydroalanine containing block copolypeptides

含脱氢丙氨酸嵌段共聚肽的合成、组装和性质

基本信息

批准号：
2202743
负责人：
Timothy Deming
金额：
$ 48.78万
依托单位：
University of California-Los Angeles
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2202743&HistoricalAwards=false
关键词：
Synthesis assembly properties dehydroalanine containing

项目摘要

With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Timothy J. Deming of the University of California-Los Angeles is preparing and studying the aqueous self-assembly of synthetic copolypeptide amphiphiles containing dehydroamino acids. Polypeptides are among the most important biopolymers and are basically long chain macromolecules consisting of amino acids linked together by a particular kind of a chemical bond called a peptide bond or link. All living organisms contain numerous polypeptides and cannot exist without them. Amphiphilic copolymers, on the other hand, are polymers that possess both water-loving and oil-loving properties. They are typically found in soaps and detergents and are also the main component of cell membranes. In this research, copolypeptides containing dehydroalanine segments will first be synthesized using a suite of chemical reaction sequences. The assemblies of these polymers will then be investigated in water in order to understand how the extended conformation of hydrophobic (oil-loving) dehydroalanine segments influences assembly structure. The synthesized polymers will also be subjected to chemical modifications in order to further understand structural changes in these assemblies when they are exposed to biological conditions that mimic those found in the human body. These studies have the potential to advance the knowledge on self-assembly of complex biopolymers and are also of relevance to the development of stimuli responsive biomaterials for therapeutic delivery applications. The research will provide interdisciplinary teaching and training of graduate and undergraduate students and unique opportunities for inclusion of underrepresented groups. The team will continue interactions and outreach with local universities with majority Hispanic student populations. Participations in “Meet the ACS Editors” events at national conferences will afford advice on preparation and review of manuscripts to young scientists and encourage URM and female junior faculty to participate in journal activities and organize ACS National Meeting symposia. This research will focus on the design, synthesis and systematic study of self-assembly of novel diblock copolypeptide amphiphiles containing poly(dehydroalanine) (ADH) segments in order to learn how the extended conformations of ADH chains of varying lengths influence self-assembled structures. Following the identification of compositions useful for the formation of ordered assemblies, ionic hydrophilic segments will be replaced with non-ionic and biocompatible poly(L-methionine sulfoxide). This modification will enable evaluation of simultaneous switching of conformation and solubility in copolypeptides. The use of non-ionic segments is also expected to impart improved downstream cell and animal compatibility. All copolypeptides will be purified by dialysis and characterized using a suite of chromatographic and spectroscopic techniques. Lastly, a biomimetic chemical modification of ADH and other segments in block copolypeptides will be investigated in order to further understand how assembled structures respond to changes in both segment conformations and solubilities. Outcomes of these studies will provide new insights on how chain conformation switching under biologically relevant conditions can enhance the development and advancement of stimuli responsive biomaterials, in particular those amenable for intracellular therapeutic delivery. The methodology developed in this research significantly lowers the barriers for synthetic access to ADH-containing copolymers. Coupled with in-depth examination of the relationships between copolypeptide composition and self-assembled structures, the knowledge gained has the potential to advance the field of biomimetic polymers.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.

在化学系大分子、超分子和纳米化学项目的支持下，加州大学洛杉矶分校的Timothy J.德明教授正在制备和研究含脱氢氨基酸的合成共聚肽两亲物的水溶液自组装。多肽是最重要的生物聚合物之一，基本上是由氨基酸组成的长链大分子，这些氨基酸通过一种特殊的化学键连接在一起，称为肽键或连接。所有的生物体都含有大量的多肽，没有它们就不能生存。另一方面，两亲性共聚物是同时具有亲水性和亲油性的聚合物。它们通常存在于肥皂和洗涤剂中，也是细胞膜的主要成分。在本研究中，我们将首先利用一套化学反应序列来合成含有脱氢丙氨酸片段的共聚肽。这些聚合物的组件，然后将在水中进行研究，以了解如何扩展的疏水性（亲油）脱氢丙氨酸片段的构象影响组装结构。合成的聚合物还将进行化学修饰，以进一步了解当它们暴露于模拟人体中发现的生物条件时这些组件中的结构变化。这些研究有可能推进复杂生物聚合物自组装的知识，也与开发用于治疗递送应用的刺激响应性生物材料有关。这项研究将为研究生和本科生提供跨学科的教学和培训，并为代表性不足的群体提供独特的机会。该团队将继续与当地大学的互动和推广，其中大多数是西班牙裔学生。在全国会议上举办的“会见美国化学会编辑”活动中，将向青年科学家提供关于编写和审查手稿的建议，并鼓励大学资源管理处和女青年教师参加期刊活动和组织美国化学会全国会议专题讨论会。本研究将致力于设计、合成和系统地研究含聚脱氢丙氨酸（ADH）链段的新型二嵌段共聚肽两亲物的自组装，以了解不同长度的ADH链的扩展构象如何影响自组装结构。在鉴定了可用于形成有序组装体的组合物之后，将用非离子和生物相容性聚（L-甲硫氨酸亚砜）替换离子亲水性片段。这种修饰将能够评估共多肽中构象和溶解度的同时转换。还预期使用非离子片段赋予改善的下游细胞和动物相容性。所有共聚肽将通过透析纯化，并使用一套色谱和光谱技术进行表征。最后，将研究ADH和嵌段共聚肽中的其他片段的仿生化学修饰，以进一步了解组装结构如何响应片段构象和溶解度的变化。这些研究的结果将提供新的见解，如何在生物相关条件下的链构象转换可以提高刺激响应性生物材料的发展和进步，特别是那些适合细胞内治疗输送。本研究中开发的方法显著降低了合成含ADH共聚物的障碍。结合对共聚肽组成和自组装结构之间关系的深入研究，所获得的知识有可能推动仿生聚合物领域的发展。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。