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/V046594/2
• 负责人: Nicholas Turner
• 金额: $ 17.83万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV046594%2F2
• 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日益增长的需求，促使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有潜力超过其生物对应物的材料。分子印迹聚合物（MIPs）是一种优雅的仿生学，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。它们代表了一种通用的、通用的、可扩展的、具有成本效益的方法来创造合成分子受体，并在分离科学、纯化、传感器和催化方面有应用。在“经典”分子印迹中，使用小的功能单体来创建结合位点。虽然这种方法已被证明是有效的，但在重结合中仍然观察到相对较高的异质性，这降低了平均结合常数，导致选择性大大降低。这一“阿喀琉斯之踵”阻碍了MIPs发挥其潜力，并导致其在特定领域的应用有限。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造成的，在印迹过程中，功能以随机的方式被引入到目标中，在聚合物基质中随后形成结合袋期间产生的错误没有留下纠正的余地。我们将通过开发一种新的两步工艺来解决这些问题，以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Fulton开发的一种方法，在模板过程中引入错误校正，以及Turner开发的另一种方法，将结合位点固定在刚性聚合物纳米颗粒“支架”中。这种杂交将把优化的结合位点“锁定”到一个更刚性的结构中——创造出新的合成仿生物，减少了异质性，同时通过组分选择结合了生物相容性。这些混合MIPs可以真正挑战和取代它们的生物对应物，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物质的发展。它们在大小和应用方面有所不同：一种是蛋白质，一种是生物活性（抗生素）药物，但这两种靶标在临床和环境环境中都具有巨大的商业潜力。监测抗生素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的环境泄漏的关键，这导致了许多其他严重问题，如细菌耐药性。蛋白质靶标证明了MIP纳米颗粒破坏配体-受体结合的能力，其中MIP本身可以具有抑制性“药物样”特性。通过这些模型，我们旨在证明所提出的新型MIP系统的有效性和潜力。该项目将使用德蒙福特大学和纽卡斯尔大学的设施来开发新方法。在一个经验丰富的跨学科项目团队的支持下，这项涵盖有机、聚合物和分析化学的提案将采用一种新的MIP合成方法，建立在现有的概念验证的基础上，并进一步发展它们，将这里描述的新颖合成工艺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，以便通过明确的步骤流程进行扩展，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

Phage display against two-dimensional metal-organic nanosheets as a new route to highly selective biomolecular recognition surfaces

针对二维金属有机纳米片的噬菌体展示作为高选择性生物分子识别表面的新途径

• DOI: 10.26434/chemrxiv-2023-6dhn7
• 发表时间: 2023
• 作者: Wood A

Utilisation of molecularly imprinting technology for the detection of glucocorticoids for a point of care surface plasmon resonance (SPR) device

• DOI: 10.1016/j.aca.2023.342004
• 发表时间: 2023-11-16
• 期刊: ANALYTICA CHIMICA ACTA
• 影响因子: 6.2
• 作者: Blackburn，Chester;Sullivan，Mark V.;Turner，Nicholas W.
• 通讯作者: Turner，Nicholas W.

Core-shell magnetic molecularly imprinted polymers: nanoparticles targeting selective androgen receptor modulators (sarms) and steroidal models

• DOI: 10.1088/2632-959x/acce52
• 发表时间: 2023-04
• 期刊: Nano Express
• 影响因子: 3
• 作者: Mark V. Sullivan;B. Dean;Aiden Mates;Maria Elizabeth Farrow;Connor Fletcher;Maddie German;Riya M Patel;N. Turner