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.

分子印迹涉及在聚合物中制造结合口袋，该结合口袋对于目标化合物具有化学和形状特异性。与抗体和酶等生物分子识别元件相比，这些“智能塑料”具有鲁棒性。他们也有能力在极端的环境条件下工作。然而，它们有时可能缺乏必要的特异性/亲和力。适体是DNA/RNA的小片段，其具有靶向蛋白质和小分子并以高特异性和亲和力与它们结合的能力。它们无毒，是抗体的有吸引力的替代品。由于它们对酶和化学降解的敏感性，它们主要用于研究，尽管这种情况正在慢慢改变，并且它们正在变得具有商业意义。全球适体市场预计到2020年将达到24亿美元，高于2015年的11亿美元。一项由EPSRC支持并由PI（分子印迹专家）领导的为期12个月的概念验证研究，通过将适体纳入分子印迹聚合物（MIP）中来创建新型混合材料。简而言之，适体结构被修改以允许其直接掺入聚合物中，因此它将保持其形状，同时免受环境条件的影响。这些“aptaMIPs”表现出优异的分子识别能力，在稳定性和特异性靶点识别方面，与MIPs和适体相比有了显著的改进，有效地保持了两类材料的最佳性能。该提案旨在通过为期两年的研究来探索aptaMIPs的潜力，研究用于创建这些新材料的核心化学。我们将在试点研究结果的基础上，创造出具有高商业潜力的有用、有效的材料。本提案中的研究将集中在：（i）确定正确的连接体化学;（ii）为所有四种碱基开发可聚合的修饰;（iii）确定需要多少个连接体;（iv）确定这些连接体的最佳位置。对这四点的深入研究将使我们能够充分了解适体如何将自身融入聚合物的关键化学过程，并通过这一过程，使我们能够理解是什么造就了一个好的aptaMIP以及为什么。除此之外，还将分析所使用的合成策略，以确保这些杂交体的产生简单有效。这些靶点在大小和应用上有所不同：蛋白质和生物活性药物，但这两种靶点都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。除了PI，两个项目合作伙伴组成了研究团队：Watts小组是试点研究的合作者，位于马萨诸塞州大学RNA治疗研究所（一所世界领先的新型适体合成学校）。Aptamer Group是一家位于约克的商业适体开发公司，总部位于纽约，是一家致力于核酸适体开发的公司。他们的专业知识将通过提供已知的寡聚体序列使该项目受益，这些序列将作为我们研究的基础并获得专业仪器。该项目的影响将得到他们对适体领域和商业前景的详细了解的支持。整个团队的经验将使这个跨学科的提案获得成功，涵盖聚合物，核酸，蛋白质和分析化学领域。我们将把aptaMIP从现有的概念验证阶段开发出来，并将它们及其合成过程开发成人工分子识别领域的可行竞争对手，准备应用于可以利用其功能的系统中。

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

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.

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