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.

常见的遗传遗传疾病囊性纤维化（CF）的特征是阴离阴离子在整个体内跨细胞边界（或膜）衬里管道和管道。拟议的研究旨在开发能够在细胞膜上运输阴离子的化学物质。这些合成转运蛋白可能用于开发一种恢复阴离子转运CF组织的疗法。他们还应该有价值作为生物医学研究的工具。在CF中，特定蛋白质的故障，囊性纤维化跨膜电导调节剂（称为CFTR）会导致整个体内的管道和管子被厚实的粘性粘液阻塞。在肺中，这会触发一个恶性的感染和炎症循环，破坏肺组织，导致呼吸困难，较差的生活质量和过早的死亡。CFTR通常在衬里的细胞表面上发现，在该细胞表面上，它可以用作anions anions of inions of Anions of Anions of Conions and conloride and BiCarybonyboybyaly。通过控制氯化物以及盐和水的运动，CFTR润滑导管和试管，而碳酸氢盐对于正常的粘液形成和运动至关重要。一种CF治疗的新方法是使用阴离子的CFTR替代疗法（CFTR替代疗法”（离子转运蛋白选择性含量）。阴离子是小分子，它们通过在生物膜呈现的屏障中转移阴离子来模仿阴离子通道的作用。通过吸入将其输送到肺部后，阴离子可以将其插入细胞膜，替代缺失的CFTR活性并在一段时间内恢复正常的粘液转运。为了测试这种方法的可行性，必须开发合适的阴离子。特别是，活动必须很高（可以使用少量），并且分子必须在活细胞中得到证明的有效性（与合成模型膜相反）。独立工作布里斯托尔和南安普敦的团队为此问题做出了重大贡献，为最活跃的无活跃的摩底摩托车做出了重大贡献。在拟议的工作中，他们将联合起来弥合“原则证明”和有意义的，潜在的治疗性生物学活性之间的差距。为了开发用于CFTR旁路治疗的新型阴离子，我们寻求强烈结合的化学物质，易于结合，易于插入细胞膜，并满足药物样分子的规则。我们将通过融合布里斯托尔和南安普敦阴离子的元素来形成新型阴离子载体来创建如此小的分子。我们将确定阴离子的紧密结合氯化物和碳酸氢盐的结合，以及它们在合成模型膜中的这些阴离子如何轻易传递。对于选定的化学物质，我们将使用复杂的电气方法在模型膜上进行测试，以建立其确切的作用机理。为了鉴定有效的活细胞的阴茎，我们将使用工程设计的细胞来表达对阴离子敏感的荧光蛋白来筛选大量分子以进行运输活性。证明最佳传递性和阴离子转运活性的化合物将使用在CF肺部空气通道的细胞中进行进一步的生物学测试。首先，我们将研究阴离子是否会恢复盐和水转运到这些细胞。然后，我们将确定阴离子是否促进粘液转运。最后，我们将对毒性和其他特性进行初步测试，以评估阴离子是否可能成功作为药物。如果结果有利，我们的研究将为基于阴离子的CFTR替换疗法提供有说服力的案例，为与医疗和工业伙伴合作的药物开发计划铺平了道路。

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

Anthracene Bisureas as Powerful and Accessible Anion Carriers.

• DOI: 10.1002/chem.201800508
• 发表时间: 2018-04-20
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Dias CM;Valkenier H;Davis AP
• 通讯作者: Davis AP