Synthetic Anionophores with Therapeutic Potential - a Coordinated Two-Centre Approach

具有治疗潜力的合成阴离子载体——协调的两中心方法

• 批准号: EP/J00961X/1
• 负责人: Anthony Davis
• 金额: $ 87.03万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ00961X%2F1
• 关键词: Synthetic; Anionophores; Therapeutic; Potential; Coordinated

The common life-shortening inherited disease cystic fibrosis (CF) is characterised by defective anion transport across cell borders (or membranes) lining ducts and tubes throughout the body. The proposed research aims to develop chemicals capable of transporting anions across cell membranes. These synthetic transporters might be used to develop a therapy that restores anion transport to CF tissues. They should also have value as tools for biomedical research.CF affects over 8,500 individuals in the UK of whom 60% are less than 20 years old. In CF, malfunction of a particular protein, the cystic fibrosis transmembrane conductance regulator (termed CFTR) causes ducts and tubes throughout the body to become blocked by thick, sticky mucus. In the lungs, this triggers a vicious cycle of infection and inflammation that destroys lung tissue, leading to breathing difficulties, poor quality of life and premature death.CFTR is normally found on the surface of cells lining ducts and tubes, where it acts as a passive gated pathway for the movement of anions, such as chloride and bicarbonate. By controlling chloride and hence salt and water movements, CFTR lubricates ducts and tubes, while bicarbonate is critical for normal mucus formation and movement.A novel approach to CF treatment is "CFTR replacement therapy" with anionophores (ion transporters selective for anions). Anionophores are small molecules that mimic the actions of anion channels by transferring anions across the barrier presented by biological membranes. Following their delivery to the lungs by inhalation, anionophores could insert into the cell membrane, replace missing CFTR activity and restore, for a period, normal mucus transport. To test the feasibility of this approach suitable anionophores must be developed. In particular, activities must be high (so that small amounts can be used), and the molecules must have proven effectiveness in live cells (as opposed to synthetic model membranes).Working independently the teams at Bristol and Southampton have made significant contributions to this problem, producing and studying anionophores which are among the most active available. In the proposed work they will join forces to bridge the gap between "proof-of-principle" and meaningful, potentially therapeutic, biological activity.To develop novel anionophores for CFTR bypass therapy, we seek chemicals which bind anions strongly, insert easily into cell membranes and which satisfy rules for drug-like molecules. We will create such small molecules by fusing elements of the Bristol and Southampton anionophores to form novel anion carriers. We will determine how tightly the anionophores bind chloride and bicarbonate and how easily they pass these anions across synthetic model membranes. For selected chemicals, we will perform tests in model membranes using sophisticated electrical methods to establish their exact mechanism of action.To identify anionophores that are effective in live cells, we will use cells engineered to express an anion-sensitive fluorescent protein to screen large numbers of molecules for transport activity. Compounds that demonstrate optimal deliverability and anion transport activity will be subjected to further biological testing using cells that line the air passages of CF lungs. First, we will investigate whether anionophores restore salt and water transport to these cells. Then, we will determine whether anionophores promote mucus transport. Finally, we will perform preliminary tests for toxicity and other properties to assess whether the anionophores are likely to succeed as drugs. If results are favourable our studies will yield a persuasive case for anionophore-based CFTR replacement therapy, paving the way for a programme of drug development in collaboration with medical and industrial partners.

常见的缩短寿命的遗传性疾病囊性纤维化(CF)的特征是阴离子跨细胞边界(或膜)运输缺陷，衬里的导管和管子遍布全身。这项拟议的研究旨在开发能够跨细胞膜运输阴离子的化学物质。这些合成的转运蛋白可能被用来开发一种治疗方法，恢复阴离子向CF组织的运输。它们还应该作为生物医学研究的工具。在英国，CF影响着8500多人，其中60%的人年龄不到20岁。在CF中，囊性纤维化跨膜电导调节因子(称为CFTR)是一种特定蛋白质的故障，它会导致全身的导管和管子被粘稠的粘液堵塞。在肺部，这会触发感染和炎症的恶性循环，破坏肺组织，导致呼吸困难、生活质量下降和过早死亡。CFTR通常存在于管道和管道内的细胞表面，在那里它充当阴离子移动的被动门控路径，如氯化物和碳酸氢盐。通过控制氯化物，从而控制盐和水的运动，CFTR润滑管道和管子，而重碳酸盐对于正常的粘液形成和移动是关键的。治疗CF的一种新方法是用阴离子载体(对阴离子具有选择性的离子转运体)进行CFTR替代疗法。阴离子载体是一种小分子，它通过将阴离子转移到生物膜提供的屏障上来模拟阴离子通道的作用。在通过吸入进入肺部后，阴离子载体可以插入细胞膜，取代缺失的CFTR活性，并在一段时间内恢复正常的粘液运输。为了测试这种方法的可行性，必须开发合适的阴离子载体。特别是，活性必须很高(这样才能使用少量)，分子必须在活细胞中具有被证明的有效性(与合成模型膜相反)。布里斯托尔和南安普顿的团队独立工作，为这个问题做出了重大贡献，生产和研究了现有最活跃的阴离子载体之一。在拟议的工作中，他们将联手弥合“原则证明”和有意义的、潜在的治疗性生物活性之间的差距。为了开发用于CFTR旁路治疗的新型阴离子载体，我们寻找与阴离子结合强烈、容易插入细胞膜并满足类药物分子规则的化学物质。我们将通过融合布里斯托尔和南安普顿阴离子载体的元素来创建这样的小分子，以形成新型的阴离子载体。我们将确定阴离子载体与氯化物和碳酸氢盐结合的紧密程度，以及它们通过合成模型膜的难易程度。对于选定的化学物质，我们将使用复杂的电学方法在模型膜中进行测试，以确定它们的确切作用机制。为了确定在活细胞中有效的阴离子载体，我们将使用能够表达阴离子敏感荧光蛋白的细胞来筛选大量运输活性的分子。表现出最佳递送能力和阴离子传输活性的化合物将接受进一步的生物测试，使用的细胞排列在CF肺的呼吸道内。首先，我们将调查阴离子载体是否恢复了这些细胞的盐分和水的运输。然后，我们将确定阴离子载体是否促进粘液运输。最后，我们将进行毒性和其他性质的初步测试，以评估阴离子载体是否有可能成为药物。如果结果是有利的，我们的研究将为基于阴离子载体的CFTR替代疗法提供一个有说服力的案例，为与医疗和工业合作伙伴合作的药物开发计划铺平道路。

项目成果

Hexagonal Microparticles from Hierarchical Self-Organization of Chiral Trigonal Pd3L6 Macrotetracycles

• DOI: 10.1016/j.xcrp.2020.100303
• 发表时间: 2021-01
• 期刊: Cell Reports Physical Science
• 影响因子: 8.9
• 作者: Ondřej Jurček;Nonappa;Elina Kalenius;Pia Jurček;J. Linnanto;R. Puttreddy;Hennie Valkenier;N. Houbenov;M. Babiak;M. Peterek;A. Davis;R. Marek;K. Rissanen

Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs

• DOI: 10.1039/c9sc04242c
• 发表时间: 2019-11-14
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Li, Hongyu;Valkenier, Hennie;Davis, Anthony P.
• 通讯作者: Davis, Anthony P.

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.

Anion Recognition by a Bioactive Diureidodecalin Anionophore: Solid-State, Solution, and Computational Studies.

• DOI: 10.1002/chem.201800537
• 发表时间: 2018-06-07
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Jurček O;Valkenier H;Puttreddy R;Novák M;Sparkes HA;Marek R;Rissanen K;Davis AP
• 通讯作者: Davis AP

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.