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Supramolecular Systems Capable of Bio-inspired Communication and Recognition

能够进行仿生通信和识别的超分子系统

基本信息

批准号：
MR/W00657X/1
负责人：
Charlie McTernan
金额：
$ 186.04万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW00657X%2F1
关键词：
Supramolecular Systems Capable Bio inspired

项目摘要

Supramolecular Chemistry is often inspired by the functionality and complexity of nature. Whilst great strides have been made towards achieving artificial analogues of biological molecular machines, synthetic systems have been unable to match the specificity and directionality vital to the concerted processes of biology. Here, I will develop new tools to endow artificial supramolecular systems with the functionality seen in their biological counterparts. In the first four years, I will create architectures with unprecedented target binding specificity, and systems able to transfer information across biologically-relevant membranes. In the following three years, I will collaboratively apply these in biological contexts, aiming to achieve long-term impact on biomedicine and synthetic biology by creating de novo catalytic enzyme analogues, enabling the design of synthetic cellular receptors, and generating targeted drug delivery vehicles. In the longer term, this proposal will provide new ways to repair and, eventually, replace, faulty biological systems, and so to treat intractable diseases. The complexity and functionality of biological systems is due to the information-richness of biomolecules, and their controlled distribution and motion. These properties allow demanding tasks to be completed; biomachines, such as ATP synthase, work in concert across membranes, maintaining homeostasis, and information-rich enzymes transform specific molecules using targeted interactions. In contrast, the current generation of supramolecular assemblies lack the targeted recognition present in nature, and are typically unable to work in concert, as their motion cannot be orientated. This research proposal will provide tools to bridge this gap, addressing unmet challenges in Supramolecular Chemistry. I will develop interlocked architectures whose localisation in membranes enables oriented motion, acting as novel analogues of transmembrane receptors such as GPCRs, and information-rich molecular capsules with targeted functions, able to mimic the binding specificity and catalytic function of enzymes.My proposal will, firstly, develop interlocked architectures that can embed into membranes (combining my expertise in artificial molecular machines and rotaxane formation, and expertise in membrane science at King's and the Crick) and transmit information from outside the compartment to the interior. This will enable modulation of the internal environment without the signal molecule having to pass the membrane, by physically coupling the two compartments. As such, I will create novel analogues of transmembrane signalling proteins. We will use this technology to create artificial analogues of cellular receptors, with potential applications in synthetic biology and the treatment of channelopathies such as Cystic Fibrosis and Dravet Syndrome. Secondly, this proposal will combine the information-density of biological systems with the well-defined cavity of metal-organic capsules to create supramolecular capsules with a ground-breaking array of functions, enabled by precise and targeted functionalisation of the capsule, exploiting my extensive experience of self-assembled architectures. My proposal comes at a critical juncture, seeking to address emerging challenges by creating programmable and information-rich supramolecular systems.This Fellowship will create supramolecular architectures with unprecedented specificity and controlled oriented directional motion, then work with collaborators to apply these in biological contexts, aiming to achieve long-term impact on biomedical science.

超分子化学经常受到自然界的功能性和复杂性的启发。虽然在实现生物分子机器的人工类似物方面已经取得了巨大的进步，但合成系统无法匹配对生物学协调过程至关重要的特异性和方向性。在这里，我将开发新的工具，赋予人工超分子系统在其生物对应物中看到的功能。在最初的四年里，我将创建具有前所未有的目标结合特异性的架构，以及能够跨生物相关膜传递信息的系统。在接下来的三年里，我将合作将这些应用于生物学领域，旨在通过创造新的催化酶类似物，使合成细胞受体的设计成为可能，并产生靶向药物递送载体，从而对生物医学和合成生物学产生长期影响。从长远来看，这一提议将提供修复并最终替换有缺陷的生物系统的新方法，从而治疗难治性疾病。生物系统的复杂性和功能性是由于生物分子的信息丰富，以及它们的分布和运动的控制。这些属性允许完成苛刻的任务；生物机器，如ATP合成酶，跨膜协同工作，维持体内平衡，信息丰富的酶通过靶向相互作用转化特定分子。相比之下，当前一代的超分子组装缺乏自然界中存在的目标识别，并且通常无法协同工作，因为它们的运动无法定向。这项研究计划将为弥合这一差距提供工具，解决超分子化学中未遇到的挑战。我将开发联锁结构，其在膜中的定位使定向运动成为可能，作为跨膜受体（如gpcr）的新型类似物，以及具有靶向功能的信息丰富的分子胶囊，能够模拟酶的结合特异性和催化功能。我的建议是，首先，开发可以嵌入膜的互锁结构（结合我在人工分子机器和轮烷形成方面的专业知识，以及在国王学院和克里克学院的膜科学专业知识），并将信息从外部传递到内部。这将使内部环境的调制，而无需信号分子必须通过膜，通过物理耦合两个隔室。因此，我将创造新的跨膜信号蛋白类似物。我们将利用这项技术制造细胞受体的人工类似物，在合成生物学和治疗通道病（如囊性纤维化和德拉韦综合征）方面具有潜在的应用。其次，该方案将生物系统的信息密度与金属有机胶囊的定义良好的腔体结合起来，创造出具有突破性功能的超分子胶囊，通过胶囊的精确和有针对性的功能化，利用我在自组装架构方面的丰富经验。我的建议是在一个关键时刻提出的，寻求通过创建可编程和信息丰富的超分子系统来解决新出现的挑战。该奖学金将创建具有前所未有的特异性和可控定向运动的超分子结构，然后与合作者合作，将这些超分子结构应用于生物学领域，旨在对生物医学科学产生长期影响。