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：伊利诺伊大学标题：合成含N-烷基脲类肽的肝素模拟聚合物及其在抗凝试验中的评价智力优势：目前合成药物相关含糖生物聚合物类似物的方法集中在全局范围的性质，如电荷和亲水性，而不是试图了解如何利用电荷，功能和立体化学的复杂相互作用来制备上级替代品。 肝素是一种线性多糖，具有不同的取代模式，包括N-硫酸酯、O-硫酸酯和N-乙酰基。 这导致肝素在结构最复杂的GAG中排名。 然而，肝素来源于哺乳动物，具有固有的安全性问题。 因此，用合成类似物代替肝素将是非常有益的。 该提议的目的是使用N-烷基-N，N '-连接的低聚物，我们将其称为“N-烷基脲类肽”，作为合成确定的糖胺聚糖模拟物的合成多样性的一个点。 研究的中心假设是，将N-烷基脲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，从而能够快速探测针对肝素替代的合理结构-活性关系研究。 本研究的假设将通过以下具体目标进行验证：（1）利用N-烷基脲类肽/聚合物偶联物合成糖胺聚糖模拟物。 (2)用N-烷基脲类肽低聚物合成含肝素模拟片段的聚脲/聚脲。 (3)进行简单的代表性测定，以衡量合成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，蛋白质结合合成大分子和糖功能化聚合物。更广泛的意义：该提案中包含的工作代表了制备合成GAG模拟物的新策略，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。 这项研究将提供重点突出，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入辛辛那提大学的学生融入社会。 转学生可以有较低的保留率，较长的时间毕业，并降低最终GPA比他们的“传统”的学生同行。 影响转学生融入的因素之一是有机会与教授一起进行研究。 PI将针对转学生在他的实验室进行本科研究的机会。 本科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.