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

该研究计划的重点是创建和表征预组织的天然和非天然的基于聚脯氨酸（糖）的肽支架，具有模仿植物和动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，我们将制备和研究功能化的两亲性聚脯氨酸II单螺旋的结构特性，其具有单，双或三个两亲性面，旨在模拟植物结构蛋白的功能[项目A]。在第二个项目中，我们将准备和研究旨在模拟胶原蛋白功能特性的两亲性聚脯氨酸三螺旋的自组装和结构特性[项目B]。获得明确定义的，同质的植物和动物启发的结构蛋白模拟物提供了一个不可或缺的工具，研究在植物和哺乳动物细胞的细胞外基质的分子识别事件知之甚少。这种方法克服了目前蛋白质表达的限制，这些限制导致对翻译后修饰如糖基化几乎没有控制的异质混合物。从长远来看，我们将探索这些肽支架在细胞递送中的应用，同时也将其作为具有抗菌、抗肿瘤和免疫调节特性的治疗装置用于医学和人工组织工程。此外，这项研究将解决现有的差距，我们的知识如何糖基化影响的结构和功能的结构蛋白在活的生物体和螺旋手性如何影响的聚脯氨酸单和三螺旋的结构和生物学特性。与UofM医学院研究人员的现有合作以及与马尼托巴材料研究所材料化学家的新合作将用于在独特的多学科研究环境中培养学生，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。参与这些研究的学生将在加拿大经济的生物制药和生物技术领域受到独特的培训和高度期望。

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.