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

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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.