Synthetic Anion Carriers for Biomedical Applications

用于生物医学应用的合成阴离子载体

• 批准号: EP/F03623X/1
• 负责人: Anthony Davis
• 金额: $ 78.29万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF03623X%2F1
• 关键词: Synthetic; Anion; Carriers; Biomedical; Applications

Cystic fibrosis (CF) is one of the most common genetic diseases. Like many such illnesses, it is caused by the malfunction of a particular protein, the Cystic Fibrosis Transmembrane Conductance Regulator (or CFTR). In normal people CFTR resides in the membranes of cells and serves as a channel through which anions, such as chloride ions, can enter or leave the cell. Its role is especially important in the lungs, as this flow of anions helps to maintain the system which keeps the lungs clean. If the CFTR is missing, or fails to work properly, the lungs become full of sticky mucous and vulnerable to infection. In the UK, patients with CF usually die from lung disease before the age of 30.A possible approach to CF treatment is channel replacement therapy . In principle, the cell in the lungs could be provided with synthetic compounds which would mimic the action of CFTR, allowing anions to pass through the membranes. The idea has been difficult to try out, because of a lack of suitable compounds. However, we have recently discovered a family of molecules, termed cholapods , which have the necessary properties. Firstly they are made largely of hydrocarbon, and will therefore locate in cell membranes rather than aqueous solution. Secondly they have high affinities for anions such as chloride, which they can extract from water. Thirdly they can move through the membranes, carrying the anions with them. By binding chloride ions on one side and releasing them on the other, they allow the anions to cross the membrane, mimicking the overall action of CFTR. There seems a genuine prospect for developing cholapods, or related anionophores (anion carriers), into treatments for CF. However, further studies are necessary before a full biomedical programme can be considered. We need anionophores which are optimised in key respects (effectiveness as carriers, low toxicity, ease of delivery to cells). We also need to show that they can operate in natural cell membranes, as well as the simpler synthetic models used in most of our experiments. We will begin by completing a full study of the cholapods in the synthetic membranes. In particular, we will use electrical methods to achieve a detailed understanding of the transport process. We are especially interested in finding out which step (anion extraction, movement across membrane etc.) is the slowest, and is therefore rate-determining . We can then work to improve this step. We will also prepare and study a range of new examples, so that we can determine structure-activity relationships. By combining the two approaches we will identify optimal cholapods for biological studies. We will also explore some novel, cholapod-inspired structures. These contain key features of the original design, but are different in ways which might improve performance (e.g. by speeding up movement through the membrane).Once the anionophores have been optimised in synthetic membranes, they will be tested in natural systems. Electrical studies in individual cells will be followed by experiments in cultured epithelia (layers of cells which mimic the lining of the lungs). We will perform preliminary tests for toxicity and other properties relating to druggability (absorption, metabolism etc.). If results are favourable, these studies should provide proof of principal for anionophore-based channel replacement therapy for CF patients.

囊性纤维化（CF）是最常见的遗传性疾病之一。像许多这样的疾病一样，它是由一种特定的蛋白质，囊性纤维化跨膜传导调节器（或CFTR）的功能障碍引起的。在正常人中，CFTR存在于细胞膜中，作为阴离子（如氯离子）进入或离开细胞的通道。它的作用在肺部尤其重要，因为这种阴离子的流动有助于保持肺部清洁的系统。如果CFTR缺失或不能正常工作，肺部就会充满粘性粘液，容易受到感染。在英国，CF患者通常在30岁之前死于肺部疾病。CF治疗的一种可能方法是通道替代疗法。原则上，肺中的细胞可以提供模拟CFTR作用的合成化合物，允许阴离子通过膜。由于缺乏合适的化合物，这个想法很难试验。然而，我们最近发现了一个家族的分子，称为胆足，具有必要的性质。首先，它们主要由碳氢化合物组成，因此将位于细胞膜而不是水溶液中。其次，它们对氯离子等阴离子有很高的亲和力，可以从水中提取。第三，它们可以携带阴离子穿过膜。通过在一侧结合氯离子并在另一侧释放它们，它们允许阴离子穿过膜，模仿CFTR的整体作用。似乎有一个真正的前景的发展胆足，或相关的阴离子载体（阴离子载体），为CF的治疗。然而，在考虑全面的生物医学计划之前，还需要进一步的研究。我们需要在关键方面进行优化的阴离子载体（作为载体的有效性，低毒性，易于递送到细胞）。我们还需要证明它们可以在天然细胞膜中运行，以及我们大多数实验中使用的更简单的合成模型。我们将开始完成对合成膜中的胆足类的全面研究。特别地，我们将使用电学方法来实现对输运过程的详细理解。我们特别感兴趣的是找出哪一步（阴离子提取，跨膜运动等）。是最慢的，因此是速率决定的。然后我们可以努力改进这一步。我们还将准备和研究一系列新的例子，以便我们可以确定结构-活性关系。通过结合这两种方法，我们将确定最佳的胆足类生物学研究。我们还将探索一些新颖的，胆足类启发的结构。这些包含了原始设计的关键特征，但在可能提高性能的方式上有所不同（例如通过加速穿过膜的运动）。一旦阴离子载体在合成膜中得到优化，它们将在自然系统中进行测试。在单个细胞中进行电学研究之后，将在培养的上皮细胞（模拟肺内层的细胞层）中进行实验。我们将对毒性和其他与可药用性（吸收、代谢等）相关的性质进行初步测试。如果结果是有利的，这些研究应提供证据的原则为CF患者的阴离子载体为基础的通道替代疗法。

项目成果

Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution.

• DOI: 10.1002/chem.201504057
• 发表时间: 2016-02
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Edwards, Sophie J.;Marques, Igor;Dias, Christopher M.;Tromans, Robert A.;Lees, Nicholas R.;Felix, Vitor;Valkenier, Hennie;Davis, Anthony P.
• 通讯作者: Davis, Anthony P.

Pharmacological therapy for cystic fibrosis: From bench to bedside

• DOI: 10.1016/s1569-1993(11)60018-0
• 发表时间: 2011-06-01
• 期刊: JOURNAL OF CYSTIC FIBROSIS
• 影响因子: 5.2
• 作者: Becq, Frederic;Mall, Marcus A.;Zegarra-Moran, Olga
• 通讯作者: Zegarra-Moran, Olga

Potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- currents by the chemical solvent tetrahydrofuran.

化学溶剂四氢呋喃增强囊性纤维化跨膜电导调节器 (CFTR) Cl-电流。

• DOI: 10.1080/09687680802487967
• 发表时间: 2008
• 期刊: Molecular membrane biology
• 作者: Hughes LK

High-affinity anion binding by steroidal squaramide receptors.

类固醇方酰胺受体的高亲和力阴离子结合。

• DOI: 10.1002/anie.201411805
• 发表时间: 2015-04-07
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Edwards, Sophie J.;Valkenier, Hennie;Busschaert, Nathalie;Gale, Philip A.;Davis, Anthony P.
• 通讯作者: Davis, Anthony P.