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

含有 N-烷基脲类肽的肝素模拟聚合物的合成及其在抗凝试验中的评价

• 批准号: 1206150
• 负责人: Neil Ayres
• 金额: $ 27.5万
• 依托单位: University of Cincinnati Main Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1206150&HistoricalAwards=false
• 关键词: Synthesis; Heparin; mimicking; polymers; containing

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.

ID: MPS/DMR/BMAT(7623) 1206150 PI: Ayres， Neil ORG: University of辛辛那提标题：含n -烷基脲类肽的肝素模拟聚合物的合成及其在抗凝血试验中的评价目前合成具有药学意义的含糖生物聚合物类似物的方法关注的是电荷和亲水性等全局性质，而不是试图理解电荷、功能和立体化学之间的复杂相互作用如何被利用来制备一种更好的替代品。肝素是一种线性多糖，具有不同的取代模式，包括n -硫酸盐、o -硫酸盐和n -乙酰基。这导致肝素是结构最复杂的gag之一。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。本提案的目的是使用N-烷基-N，N'连接的低聚物，我们称之为“N-烷基脲肽”，作为合成定义的糖胺聚糖模拟物的合成多样性点。研究的中心假设是，将n -烷基脲类肽与糖功能化聚合物结合将产生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结构-活性关系研究。研究假设将通过以下具体目标进行验证：(1)利用n -烷基脲肽/聚合物偶联物合成糖胺聚糖模拟物。(2)利用n -烷基脲类肽低聚物合成具有模拟肝素片段的聚脲/聚氨酯。(3)进行简单的代表性试验，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提供一个新的平台，用于研究控制序列聚合物、蛋白质结合合成大分子和糖功能化聚合物。更广泛的影响：本提案中包含的工作代表了制备合成GAG模拟物的新策略，并有可能在包括生物材料，仿生化学和聚合物-生物分子相互作用在内的科学领域取得进展。本研究将提供重点突出、设计合理的研究生项目和本科生学习模块。除了预期的科学成果之外，PI还计划了一些活动，以促进从社区学院和其他机构转到辛辛那提大学的学生的融合。与“传统”学生相比，转学生的留校率更低，毕业时间更长，最终gpa也更低。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。该PI将以转学生为目标，在他的实验室进行本科研究。本科研究人员将获得从研究计划中包含的单个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。