Exploration of Linking Chemistry in the Design of Aptamer-Molecularly Imprinted Polymer Hybrids (aptaMIPs)

适配体分子印迹聚合物杂化物 (aptaMIPs) 设计中连接化学的探索

• 批准号: EP/S003339/1
• 负责人: Nicholas Turner
• 金额: $ 37.72万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS003339%2F1
• 关键词: Exploration; Linking; Chemistry; Design; Aptamer

Molecular imprinting involves making a binding pocket in a polymer which is chemically and shape specific for the target compound. These "smart plastics" offer robustness compared to biological molecular recognition elements such as antibodies and enzymes. They also have the ability to work in extreme environmental conditions. However, they can sometimes lack the necessary specificity/affinity. Aptamers are small pieces of DNA/RNA that have the ability to target proteins and small molecules and bind to them with high specificity and affinity. They are not toxic and are attractive alternatives to antibodies. They have been used primarily in research due to their susceptibility to enzymatic and chemical degradation, though this is slowly changing and they are becoming commercially relevant. The global aptamers market is projected to reach $2.4 billion by 2020, up from $1.1 billion in 2015.A 12-month proof-of-concept study, supported by the EPSRC and led by the PI (a molecular imprinting specialist), created novel hybrid materials made by incorporating aptamers into molecularly imprinted polymers (MIPs). In simple terms, the aptamer structure is modified to allow it to be directly incorporated into a polymer, so it will hold its shape while being protected from environmental conditions. Novel, high affinity and stable materials were created.These "aptaMIPs" demonstrated exceptional molecular recognition and offer significant improvements on both MIPs and aptamers in terms of stability, and specific target recognition, effectively maintaining the best properties of both classes of materials. This proposal seeks to explore the potential of aptaMIPs through a two year study into the core chemistry used to create these novel materials. We will build on the results of the pilot study and create useful, effective materials with high commercial potential.The research in this proposal will focus on: (i) Identifying the right linker chemistry;(ii) Developing polymerisable modifications for all four bases;(iii) Identifying how many linkers are needed;(iv) Identifying the best position for these linkers. An in-depth study on these four points will enable a full understanding of the key chemistry of how the aptamer incorporates itself into the polymer and, through this, allow us to understand what makes a good aptaMIP and why. Alongside these the synthetic strategies used will be analysed to ensure the creation of these hybrids is simple and effective.Two targets have been selected to study these chemistries. These differ in size and application: a protein and a bioactive drug, but both targets have significant commercial potential. Through these model systems we aim to demonstrate the validity and potential of aptaMIP materials.Alongside the PI, two project partners form the research team:The Watts group were collaborators on the pilot study and are based at the University of Massachusetts RNA Therapeutics Institute (a world leading school in novel aptamer synthesis). They will support the proposal through access to state-of-the-art synthesis equipment, combined with know-how in oligomer synthesis and application.Aptamer Group are a commercial aptamer development company based in York. Their expertise will benefit the project by providing the known oligomer sequences which will act as the basis for our studies and access to specialised instrumentation. The impact of the project will be supported by their detailed knowledge of the aptamer field and commercial outlook.The experience of the whole team will allow this interdisciplinary proposal, covering the fields of polymer, nucleic acid, protein and analytical chemistries to succeed. We will take aptaMIPs from the existing proof-of-concept stage and develop them, and their synthetic process, into viable competitors in artificial molecular recognition, ready for application in systems where their functionality can be exploited.

分子烙印涉及在聚合物中制作一个结合袋，该聚合物是化学上特有的，对靶化合物具有特异性。与生物分子识别元件（例如抗体和酶）相比，这些“智能塑料”具有鲁棒性。他们还具有在极端环境条件下工作的能力。但是，他们有时可能缺乏必要的特异性/亲和力。适体是小块的DNA/RNA，具有靶向蛋白质和小分子并具有高特异性和亲和力与它们结合的能力。它们没有毒性，并且是抗体的有吸引力的替代品。由于它们对酶促和化学降解的敏感性，它们主要用于研究，尽管这种情况正在缓慢变化，并且它们正在商业上相关。到2020年，全球适应性市场预计将达到24亿美元，高于2015年的11亿美元。由EPSRC支持的12个月概念证明研究，由PI（分子烙印专家）领导，创建了通过将Aptamers纳入分子印象的Polymers（Mips）而创建的新型混合材料。简而言之，对适体结构进行了修改，以使其直接掺入聚合物中，因此它可以保持其形状，同时受到保护不受环境条件的保护。创建了新颖的，高亲和力和稳定的材料。这些“ Aptamips”在稳定性和特定的目标识别方面表现出异常的分子识别，并为MIP和适体提供了显着改善，并有效地维持了两类材料的最佳特性。该建议旨在通过对用于创建这些新型材料的核心化学研究进行两年研究，探索适体的潜力。我们将基于试点研究的结果，并创建具有较高商业潜力的有用的有效材料。该提案的研究将重点介绍：（i）确定正确的接头化学；（ii）为所有四个基础开发可聚合的可修改；（iii）确定需要多少个接头；（iv）确定这些链接的最佳位置。对这四个点的深入研究将使适体如何融入聚合物的关键化学反应，并通过此过程使我们能够理解什么使良好的Aptamip以及原因。除这些外，还将分析所使用的合成策略，以确保创建这些杂种是简单有效的。已选择两个目标来研究这些化学。这些规模和应用不同：一种蛋白质和生物活性药物，但两个靶标具有巨大的商业潜力。通过这些模型系统，我们旨在证明Aptamip材料的有效性和潜力。同时PI，两个项目合作伙伴组成了研究团队：Watts Group是试点研究的合作者，并位于马萨诸塞州RNA RNA Therapeutics Institute（一所新型Aptamer合成中的世界领先学校）。他们将通过使用最先进的合成设备来支持该提案，并结合寡聚合成和应用的专业知识。AppamerGroup是位于约克的商业适体开发公司。他们的专业知识将通过提供已知的低聚物序列来使该项目受益，该序列将充当我们的研究和获得专业仪器的基础。该项目的影响将得到他们对适体领域和商业前景的详细知识的支持。整个团队的经验将允许该跨学科的建议，涵盖聚合物，核酸，蛋白质，蛋白质和分析化学的领域取得成功。我们将从现有的概念验证阶段将APTAMIPS纳入人工分子识别的可行竞争者，并准备在可以利用其功能的系统中应用。

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

Detection of selective androgen receptor modulators (SARMs) in serum using a molecularly imprinted nanoparticle surface plasmon resonance sensor

• DOI: 10.1039/d2tb00270a
• 发表时间: 2022-06-06
• 期刊: JOURNAL OF MATERIALS CHEMISTRY B
• 影响因子: 7
• 作者: Henderson, Alisha;Sullivan, Mark, V;Turner, Nicholas W.
• 通讯作者: Turner, Nicholas W.

Hybrid aptamer-molecularly imprinted polymer (AptaMIP) nanoparticles selective for the antibiotic moxifloxacin

对抗生素莫西沙星具有选择性的混合适体分子印迹聚合物（AptaMIP）纳米颗粒

• DOI: 10.1039/d1py00607j
• 发表时间: 2021
• 期刊: Polymer Chemistry
• 影响因子: 4.6
• 作者: Sullivan M

Generation of High-Affinity Aptamer-MIP Hybrid Nanoparticles.

高亲和力适体-MIP 混合纳米颗粒的生成。

• DOI: 10.1007/978-1-0716-1629-1_9
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sullivan M

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.