New Synthetic Chaperones to Enhance Protein Activity

3D结构是生物功能、活性水平和蛋白质本质的基础。蛋白质与其配体之间的关键相互作用，尽管是一个小分子或另一种蛋白质利用特定的结构。因此，一级、二级和三级结构的变化会导致蛋白质行为的重大变化。这些变化可以是由结构改变引起的酶活性的简单增加或减少（由另一分子实体的存在引起）；直到在糖尿病和阿尔茨海默氏症等疾病中观察到的错误折叠发病机制。自然界已经发展出控制机制来调节许多生物系统的结构/功能。这里的大想法是，具有特殊选择性，亲和力和生物相容性的纳米级聚合物材料将作为这些控制机制的仿生学，并影响蛋白质的行为。我们的愿景是，这些材料将作为特定角色的人工伴侣，以单一的设计过程开辟一个新的生物灵感材料领域，但有多种应用。提出的研究方案是使用分子印迹原理开发这些人工仿生学的统一设计方法。分子建模技术将识别目标结合位点以及兼容的聚合物组分。这些简单，优雅的仿生学结合了与给定靶标互补的具有立体和化学功能的结合位点，因此代表了一种通用，通用，可扩展，具有成本效益的合成分子受体的方法。它们目前用于分离科学、纯化、传感器和催化；但这一提议将扩大它们的应用范围，使这项技术发挥其真正的潜力。在活性1和活性2中，包括aptaMIPs在内的纳米级MIPs（以PI为主要载体的核酸杂交）将靶向特定结合位点（表位或更大结构域），目的是调节其靶标的功能。将探索在相关环境中增强或抑制酶活性的能力，同时了解这些材料如何相互作用，以及组合物/靶点如何产生所需的活性。在活动3和4中，将探索引导蛋白质折叠成特定结构的能力。通过提供有利于结合特定形状或构象的MIPs，我们将研究错误折叠的创建，以生产用于进一步使用的生物材料（组织工程）。我们还将探索这些材料减少或逆转错误折叠本身的潜力，为潜在的未来治疗提供概念验证数据。在整个过程中，商业和临床相关的目标被用来增加研究的影响，但也显示了开发方法的力量。该项目将使用DMU的设施，并与经验丰富的项目团队合作，该跨学科提案涵盖蛋白质，聚合物和分析化学，将采取深入的方法来合成MIP。它将以现有的概念验证思想为基础，将新的合成过程转化为可以多种方式开发的人工伴侣的可行选择。奥克兰大学将在休假期间接待PI，他们将在此期间研究mip对折叠的影响。主持人Laura Domigan博士作为访问研究员，将在此之前访问英国学习MIP设计，以最好地支持休假目标。项目合作伙伴将全程支持该项目，在合理设计、传感器应用、圆二色专业知识和折叠经验方面具有经验。我们将开发可扩展的合成方法，通过明确的步骤流程，并考虑自动化。潜在的商业化存在于英国的工业项目合作伙伴（MIP Diagnostics和Aptamer Group）。

3D structure is fundamental to the biological function, level of activity and very nature of a protein. Key interactions between the protein and its ligand albeit a small molecule or another protein exploit specific structure. Variations in primary, secondary and tertiary structure can therefore result in significant changes in a protein's behaviour. These changes can range from a simple increase or decrease in enzymatic activity caused by alterations to its structure (caused by the presence of another molecular entity); through to the misfold pathogenesis observed in diseases such as Diabetes and Alzheimer's. Nature has developed control mechanisms to regulate structure/function in many biological systems. The big idea here is that nanoscale polymeric materials with exceptional selectivity, affinity and biocompatibility will act as biomimetics of these control mechanisms and influence protein behaviours. The vision is that these materials will act as role-specific artificial chaperones, opening a new field of bio-inspired materials with a single design process but multiple applications.The proposed programme of research is a unified design approach to the development of these artificial biomimetics using the principle of Molecular Imprinting. Molecular modelling techniques will identify target binding sites alongside compatible polymer components. These simple, elegant biomimetics incorporate binding sites bearing steric and chemical functionality complementary to a given target and as such represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors. They currently are used in separation sciences, purification, sensors and catalysis; but this proposal will broaden their application, allowing the technology to reach its true potential. In activities 1 and 2, nanoscale MIPs including aptaMIPs (nucleic acid-hybrids in which the PI is a leading proponent) will be targeted towards specific binding sites (epitope or larger domain) with the aim to modulate the function of its target. The ability to enhance or inhibit enzymatic activity in relevant environments will be explored, all while building an understanding how these materials interact, and how the composition/target site generates the desired activity.In activities 3 and 4, the ability to guide the folding of protein into specific structures will be explored. By providing MIPs that favour binding a specific shape or conformation, we will look at the creation of misfolds to produce biomaterials for further use (tissue engineering). We will also explore the potential of these materials to reduce or reverse misfolding itself, providing proof-of-concept data for potential future therapeutics.Throughout commercial and clinically relevant targets are used to increase impact of the study, but also to show the power of the developed methodologies.The project will use facilities at DMU, and with an experienced project team, this interdisciplinary proposal which covers protein, polymer and analytical chemistry will take a deep-dive approach to MIP synthesis. It will build on existing proof-of-concept ideas, translating novel synthetic processes into viable options for artificial chaperones which can be exploited in multiple ways. The University of Auckland will host the PI on sabbatical who will study effects of MIPs on folding during this period. The host Dr Laura Domigan, as a visiting researcher, will visit the UK to learn MIP design prior to this, to best support the sabbatical goals.Project partners will support the program throughout, with experience in rational design, sensor application, circular dichroism expertise and folding experience. We will develop the synthetic methods to be scalable through clear step processes, with automation in mind. Potential commercialisation exists through UK based industrial project partners (MIP Diagnostics and Aptamer Group).