Goodchild Strategic Research Centre: CFTR Folding and Function
The aim of this Strategic Research Centre (SRC) is to design new and innovative medicines to act on the CFTR protein that will make a bigger difference for more people with cystic fibrosis (CF).
Medicines like Kalydeco, Symkevi and Kaftrio, known as ‘CFTR modulators’, work by correcting the faulty ‘CFTR’ protein that causes cystic fibrosis, and have transformed the treatment of the condition. While these medicines are highly effective, there is still room for improvement. Current CFTR modulators do not restore complete CFTR function nor prevent disease progression, and do not benefit everyone with cystic fibrosis.
There is potential to design new and innovative medicines to act on the CFTR protein that will make a bigger difference for more people with cystic fibrosis. These improvements can only be made by increasing our detailed understanding of faulty CFTR proteins and exploring novel ways to correct them. These are the aims of Cystic Fibrosis Trust’s new Strategic Research Centre, an international programme of work which will be led by Professor David Sheppard based at the University of Bristol.
More information on the Background and Aims of the project is given below.
What we know about the CFTR protein
Proteins are made up of a long string of different building blocks. An important part of how a protein works is how it is assembled – or ‘folded’- from this long string into a specific three-dimensional shape.
Healthy copies of the CFTR protein are made and assembled inside the cell and then transported to the outside surface of the cell. Once they’re at the surface of the cell, the CFTR protein acts as a channel: a special pathway with a ‘gate’ that allows the controlled movement of ions to keep surfaces within our bodies, such as the lungs and the intestines, well hydrated.
Out of shape proteins
The defects in the CFTR gene that cause CF affect the CFTR protein. These errors mean that the CFTR protein either isn’t made at all, forms wrong shapes, or doesn’t stay in the correct shape for long enough and falls apart.
The most common ‘F508del’ defect prevents the CFTR protein from assembling into the correct shape. Very little of the misshapen CFTR reaches the outside surface of cells. Any that does is fragile, quickly stops working and breaks down.
Medicines for the CFTR protein
The CFTR modulator medicines work by subtly altering the shape of the faulty CFTR protein, by attaching themselves to specific parts of it, one known as the ‘TMD’. The medicines make faulty CFTR protein closer to the shape of healthy, undamaged CFTR.
Researchers have already found out that altering the shape of a different part of the CFTR protein called the NBD1 could make bigger improvements to the way that a larger range of faulty CFTR proteins work. The aim of this SRC is to investigate several different ways of changing the NBD1 part of the CFTR protein. This will provide important information for the development of new CFTR medicines in the future, that could benefit people with a wider range of errors in the CFTR gene.
The researchers will be investigating the effects of chemicals on the shape and function of faulty CFTR proteins when they become attached to the NBD1 area of the protein. They will investigate:
- Which chemicals can stabilise NBD1?
- How does a particular part of the NBD1 affect how the whole CFTR protein works?
- Exactly where do the selected chemicals attach to the CFTR protein?
- How do the selected chemicals rescue the shape of faulty CFTR proteins?
- Do the selected chemicals improve how the current CFTR modulators work?
- Do the chemicals work in a lab model of the CF airways?
Who is involved?
Principal Investigator: Professor David Sheppard, University of Bristol
- Professor Ineke Braakman, Utrecht University, The Netherlands
- Professor Cedric Govaerts, Université Libre de Bruxelles, Belgium
- Professor Isabelle Callebaut, Sorbonne University, Paris
This SRC was partly funded by the late Dr Mary Goodchild who kindly included a gift to the Trust in her Will. Dr Goodchild worked as a senior registrar at the Heath Hospital, Cardiff, specialising in the care of children who had CF, as well as making many contributions to CF research during her career. Dr Goodchild’s gift will continue to help those with CF and their families for many years to come.