Manipulating amyloid self-assembly: toward the design of functionalized proteinaceous nanostructures

众所周知，内源性蛋白质能够在生物体中自结合成执行重要生理功能的超分子结构。在过去的十年里，从细菌到哺乳动物，几乎所有物种都发现了具有关键生物学活性的淀粉样蛋白结构。淀粉样蛋白是高度组织化的蛋白质集合，其特征是具有跨β-折叠的四元构象，其中单个β-链垂直于纤维轴运行。淀粉样蛋白的机械、物理和生物特性表明，它们作为纳米材料在(生物)技术应用中具有巨大的潜力。例如，淀粉样蛋白材料最近被评估为细胞生长、药物输送系统和纳米传感器的支架。尽管淀粉样蛋白作为功能先进的软材料具有巨大的潜力，但今天淀粉样蛋白在纳米医学和纳米技术中的应用仍然受到许多问题的限制，这些问题包括：(I)对自组装机制的了解不完整，(Ii)控制淀粉样蛋白形成的困难，以及(Iii)根据肽序列预测超分子结构的挑战。*在此背景下，本研究计划的首要目标是发现操纵多肽自组装的创新策略，并构建高度有序的功能化蛋白质纳米结构。为了实现这一目标，以下三个具体目标将被解决：*1.确定调节多肽组件(超)分子结构的策略*2.构思化学方法来探测和暂时光控制淀粉样蛋白的形成*3.实施化学选择性方法使蛋白质纳米结构具有正交性功能*生命激发的蛋白质组件，包括淀粉样蛋白，最近在超分子结构的设计方面受到了极大的关注。这项研究计划将导致构建功能性蛋白质纳米结构的新策略，并将有助于淀粉样蛋白形成的基础知识。通过研究构象和物理化学性质在分子自组装中的作用，我们的目标是在分子水平上通过精确的设计来微调淀粉样蛋白的超结构。通过开发构象敏感的探针和光响应元件，我们将支持对动力学控制组装的驱动力的更好理解。总体而言，该计划将改变科学界对这些迷人的纳米结构的看法，促进基于淀粉样蛋白的功能先进生物材料的应用。因此，该计划将为加拿大的纳米技术、生命科学和生物制药部门提供新的研究机会和创新的应用途径。

Endogenous proteins are known for their ability to self-associate in living organisms into supramolecular structures that perform vital physiological functions. Over the last decade, amyloid structures that accomplish crucial biological activities have been identified in almost all species, from bacteria to mammals. Amyloids are highly organized proteinaceous assemblies that are characterized by a cross-beta-sheet quaternary conformation in which individual beta-strands are running perpendicular to the fibril axis. The mechanical, physical and biological properties of amyloids suggest that they hold great potential as nanomaterials for (bio)technological applications. For instance, amyloid based-materials were recently evaluated as scaffold for cell growth, drug delivery systems and nanosensors. Despite their tremendous potential as functional advanced soft materials, the usage of amyloids in nanomedicine and nanotechnology is still today limited by a number of issues, which include; (i) incomplete understanding of the mechanisms of self-assembly, (ii) difficulty to control amyloid formation and (iii) challenge to predict the supramolecular architecture from the peptide sequence. ******In this context, the overarching goal of this research program is to uncover innovative strategies to manipulate peptide self-assembly and to construct highly ordered functionalized proteinaceous nanostructures. Toward this goal, the three following specific aims will be addressed: ***1. Identify strategies to modulate the (supra)molecular architecture of peptide assemblies ***2. Conceive chemical approaches to probe and temporally photocontrol amyloid formation ***3. Implement chemoselective methods to orthogonally functionalize proteinaceous nanostructures*** ***Life-inspired protein assemblies, including amyloids, have recently received a huge increase of interest for the design of supramolecular structures. This research program will lead to novel strategies to construct functional proteinaceous nanostructures and will contribute to the fundamental knowledge of amyloid formation. By studying the roles of conformational and physicochemical properties in molecular self-assembly, we aim at fine-tuning the amyloid suprastructure with a precise design at the molecular level. By developing conformational-sensitive probes and photoresponsive elements, we will support a better understanding of the driving forces that kinetically control assembly. Overall, this program will transform the perception of the scientific community towards these fascinating nanostructures, fostering the applications of functional amyloid-based advanced biomaterials. Accordingly, this program will open to novel research opportunities and innovative applied avenues for Canada's nanotechnology, life sciences and biopharmaceutical sectors.