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

Project Details

Description

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.

Key findings

We have shown that molecules can be designed to serve and transmembrane anion carriers, and that this activity can be demonstrated in cells. The molecules appear to be non-toxic, so have potential to serve as treatments for channelopathies such as cystic fibrosis.
StatusFinished
Effective start/end date10/09/129/03/16