Synthesis of Heparin mimicking polymers containing N-alkyl urea peptoids and their evaluation in anticoagulation assays

ID：MPS/DMR/BMAT(7623)1206150 PI：Ayres，Neil ORG：辛辛那提大学题目：含有N-烷基尿素类肽的仿肝素聚合物的合成及其在抗凝分析中的评价INTELLECTUCTUAL：目前合成与药物相关的含糖生物聚合物的类似物的方法集中在全球范围内的性质，如电荷和亲水性，而不是试图了解如何利用电荷、官能度和立体化学的复杂相互作用来制备更好的替代品。肝素是一种线性多糖，具有不同的取代方式，包括N-硫酸盐、O-硫酸盐和N-乙酰基。这导致肝素在结构上最复杂的GAG中名列前茅。然而，肝素来自哺乳动物，具有固有的安全性问题。因此，用合成类似物取代肝素将是非常有益的。这项建议的目的是使用N-烷基-N，N‘-连接的低聚物，我们称之为“N-烷基尿素类肽”，作为合成多样性的点，用于合成定义的糖胺多糖模拟物。正在研究的中心假设是，将N-烷基尿素类肽与糖官能化聚合物相结合将导致具有高度合成通用性的糖胺聚糖模拟物，从而能够快速探索针对肝素替代的合理构效关系研究。研究假设将通过追求以下具体目标来验证：(1)利用N-烷基尿素类肽/聚合物偶联物合成糖胺多糖模拟物。(2)用N-烷基尿素类肽低聚物合成含类肝素链段的聚脲/氨酯。(3)进行简单的代表性分析，以衡量合成的糖胺聚糖模拟物的性能。该项目将为研究人员建立一个新的平台，用于研究受控序列聚合物、蛋白质结合的合成大分子和糖官能化聚合物。布罗德影响：该提案中包含的工作代表了制备合成GAG模拟物的新战略，并有可能在生物材料、仿生化学和聚合物-生物分子相互作用等科学领域取得进展。这项研究将提供有重点的、合理设计的研究生项目和本科生学习模块。除了预期的科学成果外，PI还计划开展活动，促进从社区学院和其他机构转到辛辛那提大学的学生融入社会。与“传统”学生相比，转学学生的留校率更低，毕业时间更长，期末GPA更低。影响转校生融合的因素之一是与教授进行研究的机会。PI将针对转校生在他的实验室获得本科生研究机会。本科生研究人员将获得从研究计划中包含的个人实验开发的学生学习模块，从而为项目的成功结果做出重大贡献。

ID: MPS/DMR/BMAT(7623) 1206150 PI: Ayres, Neil ORG: University of CincinnatiTitle: Synthesis of heparin mimicking polymers containing N-alkyl urea peptoids and their evaluation in anticoagulation assaysINTELLECTUAL MERIT: Current approaches to synthetic analogues of pharmaceutically relevant, sugar-containing biopolymers focus on global scale properties such as charge and hydrophilicity, rather than attempting to understand how the complex interplay of charge, functionality, and stereochemistry might be harnessed to prepare a superior alternative. Heparin is a linear polysaccharide possessing variable patterns of substitution including N-sulfate, O-sulfate, and N-acetyl groups. This results in heparin ranking among the most structurally complex GAGs. However, heparin is sourced from mammals and possesses inherent safety concerns. Therefore, replacing heparin with a synthetic analogue would be highly beneficial. The objective of this proposal is to use N-alkyl-N,N'-linked oligomers, which we have termed "N-alkyl urea peptoids," as a point of synthetic diversity for the synthesis of defined glycosaminoglycan mimetics. The central hypothesis under study is that combining N-alkyl urea peptoids with sugar-functionalized polymers will lead to glycosaminoglycan mimetics with a high degree of synthetic versatility, enabling the rapid probing of rational structure-activity relationship studies directed at heparin replacement. The research hypothesis will be tested by pursuing the following specific aims: (1) Use N-alkyl urea peptoid/polymer conjugates to synthesize glycosaminoglycan mimetics. (2) Use N-alkyl urea peptoid oligomers to synthesize polyurea/urethanes with heparin mimetic segments. (3) Perform simple representative assays to gauge the performance of the synthetic glycosaminoglycan mimetics. This project will establish a new platform for researchers to use in studying controlled sequence polymers, protein-binding synthetic macromolecules, and sugar-functionalized polymers.BROADER IMPACTS: The work contained in this proposal represents a new strategy in preparing synthetic GAG mimics and has the potential to enable progress in scientific areas including biomaterials, biomimetic chemistry, and polymer-biomolecule interactions. This research will deliver focused, rationally designed post-graduate projects and undergraduate student learning modules. Beyond the expected scientific results, the PI has planned activities to promote integration of students transferring into the University of Cincinnati from community colleges and other institutions. Transfer students can have lower retention rates, longer time-to-graduation, and lower final GPAs than their "traditional" student counterparts. One of the factors influencing the integration of transfer students is the opportunity to perform research with a professor. The PI will target transfer students for undergraduate research opportunities in his lab. The undergraduate researcher will be given student learning modules developed from individual experiments contained within the Research Plan, resulting in a significant contribution to the successful outcome of the project.