Synthetic, structural and biological studies on glycosylated amphiphilic polyproline II helices

这项拟议的研究计划专注于创建和表征预先组织的基于多聚脯氨酸(Glyco)的多肽支架，这些支架具有模拟动植物王国复杂结构蛋白的功能和生物学特性的能力。 在短期内，我们将制备和研究具有单、双或三个两亲性表面的功能化两亲性多聚脯氨酸II单螺旋的结构性质，旨在模仿植物结构蛋白的功能[项目A]。在第二个项目中，我们将制备和研究模仿胶原蛋白功能特性的两亲性多聚脯氨酸三螺旋的自组装和结构特性[项目B]。获得定义明确、均一的植物和动物启发的结构蛋白模拟物为研究植物和哺乳动物细胞外基质中鲜为人知的分子识别事件提供了不可或缺的工具。这种方法克服了目前蛋白质表达的局限性，导致了对糖基化等翻译后修饰几乎没有控制的异质混合物。从长远来看，我们将探索这些多肽支架在细胞输送中的应用，以及在医学和人工组织工程中作为具有抗菌、抗肿瘤和免疫调节特性的治疗设备的应用。此外，这项研究将解决我们在现有知识方面的空白，即糖基化如何影响生物体中结构蛋白的结构和功能，以及螺旋手性如何影响多聚脯氨酸单螺旋和三螺旋的结构和生物学特性。将利用与密歇根大学医学院研究人员的现有合作以及与马尼托巴省材料研究所材料化学家的新合作，在从有机化学、药物化学、糖生物学、微生物学、癌症研究、免疫学到材料科学的独特多学科研究环境中培训学生。参与这些研究的学生将接受独特的培训，并在加拿大经济的生物制药和生物技术部门非常受欢迎。

This proposed research program focuses on the creation and characterization of preorganized natural and unnatural polyproline-based (glyco)peptide scaffolds with the ability to mimic the functional and biological properties of complex structural proteins of the plant- and animal kingdom. In the short-term we will prepare and study the structural properties of functionalized amphiphilic polyproline II mono helices with single, double or triple amphiphilic faces designed to mimic the functions of plant-based structural proteins [project A]. In a second project we will prepare and study the self-assembling and structural properties of amphiphilic polyproline triple helices designed to mimic the functional properties of collagens [project B]. Access to well-defined, homogeneous plant- and animal-inspired structural protein mimetics provides an indispensable tool to study the poorly-understood molecular recognition events at the extracellular matrix of plants and mammalian cells. This approach overcomes current limitations in protein expression that result in heterogeneous mixtures with little control over post-translational modifications such as glycosylation. In the longer-term we will explore the use of these peptide scaffolds in cell delivery but also as therapeutic devices with antibacterial, antitumor and immunomodulatory properties in medicine and artificial tissue engineering. Moreover, this study will address existing gaps in our knowledge how glycosylation affects the structure and functions of structural proteins in living organisms and how helical chirality affects the structural and biological properties of the polyproline single- and triple helix. Existing collaborations with researchers at the Faculty of Medicine at UofM as well as new collaborations with material chemists at the Manitoba Institute for Materials will be used to train students in a unique multidisciplinary research environment ranging from Organic Chemistry, Medicinal Chemistry, Glycobiology, Microbiology, Cancer Research, Immunology to Materials Science. Students involved in these studies will be uniquely trained and highly desirable in the biopharmaceutical and biotechnology sectors of the Canadian economy.