Directed Molecular Recognition through Next-Generation Hybrid Molecular Imprinting

通过下一代混合分子印迹进行定向分子识别

• 批准号: EP/V046594/1
• 负责人: Nicholas Turner
• 金额: $ 34.42万
• 依托单位: De Montfort University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV046594%2F1
• 关键词: Directed; Molecular; Recognition; through; Next

The increasing demand for highly effective molecular recognition for sensing and separations has led researchers to search for synthetic substitutes for enzymes and antibodies with emphasis on materials with potential to outperform their biological counterparts in terms of cost, performance, stability and flexibility. Molecularly Imprinted Polymers (MIPs) are elegant biomimetics that incorporate binding sites bearing steric and chemical functionality complementary to a given target. They represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors and have uses in separation sciences, purification, sensors and catalysis. In "classical" molecular imprinting, small functional monomers are used to create the binding sites. While this method has proven generally effective, a relatively high level of heterogeneity in rebinding is still observed which lowers the average binding constant and leads to much-reduced selectivity. This "Achilles Heel" has prevented MIPs from fulfilling their potential, and has led to only their limited application in niche areas. A solution to the heterogeneity problem would unleash the transformational potential of MIPs within the multi-billion-dollar diagnostic and analytical markets.This heterogeneity arises because of the nature of the imprinting process, where functionality is introduced to the target in a random fashion, leaving no scope for the correction of errors that arise during the subsequent formation of the binding pocket in the polymeric matrix. We will address these issues by developing a novel two-step process towards the formation of imprinted polymeric nanoparticles of exceptionally high affinity and selectivity. It will exploit a method developed by Fulton that introduces error-correction into the templating process, and a separate method developed by Turner to then fix the binding site within a rigid polymeric nanoparticle "scaffold". This hybridisation will deliver optimized binding sites "locked" into a more rigid structure - creating new synthetic biomimetics with reduced heterogeneity, while incorporating biocompatibility through component selection. These hybrid MIPs can truly challenge and replace their biological counterparts - creating significant impact in the field of molecular recognition and smart materials. Two targets have been selected to drive the development of these chemistries. These differ in size and application: a protein and a bioactive (antibiotic) drug, but both targets have significant commercial potential, in clinical and environmental settings. Monitoring of antibiotics is key for understanding required effective dosage, but also for studying leakage into the environment from illegal use or overuse, which leads to numerous other serious issues such as bacterial resistance. The protein target offers a demonstration of the MIP nanoparticle ability to disrupt ligand-receptor binding, where the MIP itself can act with inhibitory "drug-like" properties. Through these models we aim to demonstrate the validity and potential of the proposed novel MIP systems. The project will use facilities at De Montfort University and Newcastle University to develop the new approach. With an experienced project team this interdisciplinary proposal, which covers organic, polymer and analytical chemistry, will take a new approach to MIP synthesis, building on existing proof-of-concept ideas, and develop them further, translating the novel synthetic processes described here into viable options for artificial molecular recognition which can be exploited in several ways. Here we will develop the synthetic methods to be scalable through clear step processes, with automation in mind. MIP Diagnostics are a UK company based in Bedford who will support the project by their detailed knowledge of MIP design, implementation, and application, with sight towards commercialisation of the technology.

对用于传感和分离的高效分子识别的需求日益增加，导致研究人员寻找酶和抗体的合成替代品，重点是在成本，性能，稳定性和灵活性方面具有超越生物对应物的潜力的材料。分子印迹聚合物是一种具有空间和化学功能的仿生材料。它们代表了一种通用的、多功能的、可扩展的、具有成本效益的方法来创建合成分子受体，并在分离科学、纯化、传感器和催化中有用途。在“经典”分子印迹中，小的功能单体用于产生结合位点。虽然这种方法已被证明是普遍有效的，但仍观察到相对高水平的再结合异质性，这降低了平均结合常数并导致选择性大大降低。这一“阿喀琉斯之踵”阻碍了MIP发挥其潜力，并导致其仅在利基领域中的有限应用。异质性问题的解决方案将释放MIP在数十亿美元的诊断和分析市场中的转型潜力，这种异质性是由于印迹过程的性质而产生的，其中功能性以随机方式引入到目标中，没有留下任何纠正聚合物基质中随后形成结合口袋期间出现的错误的余地。我们将通过开发一种新的两步法来解决这些问题，从而形成具有极高亲和力和选择性的印迹聚合物纳米颗粒。它将利用富尔顿开发的一种方法，该方法将纠错引入模板化过程，以及特纳开发的一种单独的方法，然后将结合位点固定在刚性聚合物纳米颗粒“支架”内。这种杂交将提供优化的结合位点“锁定”到更刚性的结构中-产生具有降低的异质性的新合成仿生学，同时通过组分选择结合生物相容性。这些混合分子印迹聚合物可以真正挑战和取代其生物对应物-在分子识别和智能材料领域产生重大影响。已经选择了两个目标来推动这些化学品的发展。这些靶点在大小和应用上有所不同：蛋白质和生物活性（抗生素）药物，但这两种靶点在临床和环境中都具有巨大的商业潜力。抗生素的监测是了解所需有效剂量的关键，也是研究非法使用或过度使用导致许多其他严重问题（如细菌耐药性）泄漏到环境中的关键。蛋白质靶标提供了MIP纳米颗粒破坏配体-受体结合的能力的证明，其中MIP本身可以以抑制性“药物样”性质起作用。通过这些模型，我们的目的是证明所提出的新的MIP系统的有效性和潜力。该项目将利用德蒙福特大学和纽卡斯尔大学的设施来开发新的方法。凭借经验丰富的项目团队，这一涵盖有机，聚合物和分析化学的跨学科提案将采用新的MIP合成方法，建立在现有的概念验证思想基础上，并进一步发展它们，将本文所述的新型合成过程转化为人工分子识别的可行选择，可以通过多种方式加以利用。在这里，我们将开发合成方法，通过明确的步骤过程进行扩展，并考虑自动化。MIP Diagnostics是一家总部位于贝德福德的英国公司，他们将通过对MIP设计、实施和应用的详细了解来支持该项目，并着眼于该技术的商业化。

项目成果

A molecularly imprinted polymer nanoparticle-based surface plasmon resonance sensor platform for antibiotic detection in river water and milk.

基于分子印迹聚合物纳米颗粒的表面等离子共振传感器平台，用于河水和牛奶中的抗生素检测。

• DOI: 10.1007/s00216-022-04012-8
• 发表时间: 2022
• 期刊: Analytical and bioanalytical chemistry
• 影响因子: 4.3
• 作者: Sullivan MV

Highly Selective Aptamer-Molecularly Imprinted Polymer Hybrids for Recognition of SARS-CoV-2 Spike Protein Variants.

• DOI: 10.1002/gch2.202200215
• 发表时间: 2023-06
• 期刊: GLOBAL CHALLENGES
• 影响因子: 4.9
• 作者: Sullivan, Mark V.;Allabush, Francia;Flynn, Harriet;Balansethupathy, Banushan;Reed, Joseph A.;Barnes, Edward T.;Robson, Callum;O'Hara, Phoebe;Milburn, Laura J.;Bunka, David;Tolley, Arron;Mendes, Paula M.;Tucker, James H. R.;Turner, Nicholas W.
• 通讯作者: Turner, Nicholas W.