Anion Carriers for Channel Replacement Therapy

点击翻译按钮获取中文摘要

The common, life-shortening inherited disease cystic fibrosis (CF) is characterised by defective anion transport across cell membranes. The proposed research aims to develop chemicals which are capable of transporting anions across cell membranes, and are ready for testing in humans after safety studies are completed.Almost 11,000 people live with CF in the UK and >70,000 worldwide. The disease is caused by malfunction of a protein, the cystic fibrosis transmembrane conductance regulator (termed CFTR), which allows the transport of anions (e.g. chloride and bicarbonate) across cell membranes. When CFTR is faulty or missing from the cell membrane, ducts and tubes in the body 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.A novel approach to treat the root cause of CF is "CFTR replacement therapy" using anionophores (anion carriers). Anionophores are synthetic small molecules which are designed to replace the action of CFTR, by picking up anions on one side of the membrane, carrying them across, and releasing them on the far side. After their delivery to the lungs by inhalation and insertion into cell membranes, anionophores could rescue normal levels of anion transport and, through a chain of effects, restore the healthy mucus which is easily cleared from the lungs.In earlier work, we and others have shown that it is indeed possible to design small molecules which insert into membranes and mediate transmembrane anion transport. Some of our systems are capable of very high activity approaching that of CFTR. Importantly, a few anionophores, with drug-like properties, are capable of efficient delivery to cell membranes, where they work for prolonged periods, transporting anions into and out of cells, without signs of toxicity.Based on our previous results, there is good reason to believe that anionophores could be used to treat CF. This project will take critical steps towards realising this goal. The work will be performed by a collaboration involving chemists and physiologists in Bristol, and a chemistry group in Sydney, Australia (funded separately). Initially we will work towards optimising activity in cells, identifying the best candidates for closer examination. We will then apply a series of tests on tissues lining ducts and tubes (as opposed to individual cells) designed to validate our hypothesis that anionophores can restore normal function in CF patients. Meanwhile we will perform in-depth studies on anionophore behaviour, in both synthetic and natural membranes, so that biomedical development can rest on firm foundations. This will include selectivity and mechanistic investigations, as well as fluorescence microscopy to ascertain anionophore distribution in cells. We will also test new delivery systems which could be used to help anionophores reach cell membranes. At the end of the project we will have set the stage for clinical studies, potentially leading to treatments for CF.