Exploring interactions of polar fluoroaliphatic motifs with biomolecules.

探索极性氟代脂肪族基序与生物分子的相互作用。

• 批准号: EP/X038904/1
• 负责人: David O'Hagan
• 金额: $ 80.61万
• 依托单位: University of St Andrews
• 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: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX038904%2F1
• 关键词: Exploring; interactions; polar; fluoroaliphatic; motifs

The project will explore the properties and applications of two novel organo-fluorine motifs which have emerged from an understanding that partially fluorinated aliphatics have particularly polar properties.These partially fluorinated motifs can be contrasted with super hydrophobic fluorinated perfluorcarbons, and also hydrocarbons which are nonpolar and also hydrophobic. These classes of compounds are also chemically persistent eg PFASs, and there are concerns associated with their accumulation in the environment. It emerges that an intermediate situation with fluoromethyl (-CH2F) or fluoromethylene (-CHF-) generate compounds have a much greater affinity for water and are much more susceptible to biodegradation and improved environmental performance. This programme selects two such motifs for investigation is a variety of circumstances associated with bio-actives discovery or as tools in chemical biology. These are Janus face cyclohexanes which have fluoromethylene groups (-CHF) around the ring, and particularly in a stereochemical arrangement that has the fluorines on one face of the ring and hydrogens on the other, as this offers maximum polarity. The second is the unexplored tert-buty-trifluoro motif (TBTF) which transforms the highly hydrophobic properties of a tert-butyl group and renders it much more hydrophilic. The programme is arranged into three work-packages (WPs). WP-1 will investigate the binding of analogues of the W-peptide, a high affinity agonist of an important receptor (FPR2) associated with a range of disorders extending from heart disease to Alzheimers. The interaction of W-peptide with the receptor is very well characterised. These novel motifs will be placed into specific side chains of the W-peptide to assess relative efficacy and explore binding interactions with the receptor as a means to understanding their interactions in a protein active site. WP-2 will take a surface science approach using Atomic Force Microscopy (AFM) to assess the interactions of surfaces and cantilever tips coated in monolayers of molecules terminated with the organofluorine motifs. A wide range of experiments is designed to explore the strength of interactions with polar substituents (eg RCO2-, RN4+) and the strength of interactions between the motifs themselves, and how those interactions are influenced in different ionic solutions. The study will extend to exploring the strength of interactions with double- and single- stranded DNA and DNA. This WP aims to understand interactions between the motifs and molecules found widely in biochemistry. WP-3 will extend very specifically to nucleic acids and builds on an observation that the Janus face cyclohexanes appear to interact very strongly with double stranded DNA and much less so with single stranded DNA. These studies will be explored using techniques which can detect single molecule-molecule interactions using fluorescence microscopy. We will explore if the interactions can be strengthened by increasing the number of motifs (avidity) or if two or more molecules of dsDNA will attach to one probe with several Janus face motifs (crosslinking), essentially manipulating dsDNA on the nanoscale, with applicatiosn extending to docking cargo to dsDNA for specific functions such as splicing and cross linking etc. This WP will also explore interactions with the organofluorine motifs on G-quadruplex DNA, another DNA morphology which is of great significance in the cell cycle and programmed cell death (apoptosis), the control of which has implications in treating cancerous (immortal) cells. We will modify established G-quadruplex molecules (drug candidates) with our organofluorine motifs and examine their interactions by X-ray crystallography and a range of biophysical techniques. At the end of the programme we aim to deliver new tools and knowledge which should contribute to the development of next generation therapeutics and diagnostics in healthcare.

该项目将探索两个新的有机氟基序的性质和应用，这两个基序是基于对部分氟化脂肪族具有特殊的极性性质的理解而产生的。这些部分氟化基序可以与超疏水的全氟碳化合物以及非极性和疏水的碳氢化合物进行对比。这些类别的化合物在化学上也是持久的，例如全氟辛烷磺酸，人们担心它们在环境中的积累。研究表明，具有氟甲基(-CH2F)或氟甲基(-CHF-)的中间状态生成的化合物对水的亲和力要大得多，而且更容易被生物降解和改善环境性能。该方案选择了两个这样的主题进行研究，即在与生物活性物质发现相关的各种情况下或作为化学生物学的工具。这些是Janus面环己烷，环周围有氟亚甲基(-CHF)，特别是在环的一面有氟而在另一面有氢的立体化学排列，因为这提供了最大的极性。第二个是尚未发现的叔丁基三氟基序(TBTF)，它改变了叔丁基的高度疏水性质，使其更具亲水性。该方案被安排为三个工作包(WPS)。WP-1将研究W肽类似物的结合情况，W肽是一种重要受体(FPR2)的高亲和力激动剂，与从心脏病到阿尔茨海默病的一系列疾病有关。W-肽与受体的相互作用具有很好的特性。这些新的基序将被放入W-肽的特定侧链中，以评估相对有效性并探索与受体的结合作用，以此作为了解它们在蛋白质活性部位的相互作用的一种手段。WP-2将采用表面科学的方法，使用原子力显微镜(AFM)来评估表面和悬臂尖端之间的相互作用，这些表面和悬臂尖端涂覆在以有机氟基序终止的分子的单层中。设计了一系列的实验来探索与极性取代基(如RCo2-，RN4+)的相互作用的强度，以及基序之间的相互作用的强度，以及这些相互作用在不同的离子溶液中是如何影响的。这项研究将扩展到探索双链和单链DNA和DNA相互作用的强度。本WP旨在了解生物化学中广泛存在的基序和分子之间的相互作用。WP-3将非常专门地扩展到核酸，并建立在观察到Janus面环己烷似乎与双链DNA相互作用非常强烈，而与单链DNA作用更小的基础上。这些研究将使用可以使用荧光显微镜检测单分子-分子相互作用的技术来探索。我们将探索是否可以通过增加基序的数量(亲和力)来加强相互作用，或者是否两个或更多分子的dsDNA将附着在具有几个Janus面基序的探针上(交联)，本质上是在纳米级操纵dsDNA，其应用范围扩展到将货物对接到dsDNA上，以实现特定功能，如剪接和交联等。该WP还将探索与G-四链DNA上的有机氟基序的相互作用，G-四链DNA是另一种在细胞周期和程序性细胞死亡(细胞凋亡)中具有重要意义的DNA形态，对其的控制在治疗癌症(永生)细胞方面具有重要意义。我们将用我们的有机氟基序修饰已建立的G-四链分子(候选药物)，并通过X射线结晶学和一系列生物物理技术检查它们的相互作用。在计划结束时，我们的目标是提供新的工具和知识，这些工具和知识应该有助于医疗保健领域下一代治疗和诊断的发展。