Acting mechanisms of Ivacaftor and Lumacaftor

Question

Hello, I have a question about the acting mechanisms of Ivacaftor and Lumacaftor. In how far do they change the molecule respectively which biochemical processes are involved?
Best regards

Answer

Dear questioner,
the cause of CF are mutations in the so-called CFTR gene, that codes for a chloride channel, located in the cell membrane of epithelial cells. The resulting transport defect of electrolyte ions at the mucosa of different organs, especially the lung, causes the clinical picture of CF. Ivacaftor is a selective potentiator of the CFTR-protein, that means Ivacaftor increases the CFTR channel-opening-activity (“Gating”) and increases like this the chloride transport. The positive effect of Ivacaftor however, requires enough CFTR molecules in the cell membrane (like e.g. in case of the mutation G551D). In case the much more frequent mutation F508del is underlying as a cause of CF, the problem is however, that the defective CFTR-protein does not reach the cell membrane at all, but is even before eliminated in the cell. Lumacaftor is a so-called corrector of the CFTR, which reduces the destruction of the defective protein via binding to it, so that the defective protein can reach the cell membrane to a larger extent again. Here vice versa, Ivacaftor can act then as a potentiator and restore the impaired function, and this is the reason why at the moment the combination of both substances are tested in clinical studies.

The exact mechanism of Ivacaftor repsectively Lumacaftor is not totally enlightened in the end. Both substances have been discovered by a screening of large substance data bases in the high-throughput procedure due to their positive effect on the CFTR function – without knowing the mechanism hereby. The CFTR protein is built up by different domains (MSD1, MSD2, NBD1 and R)- Lumacaftor has a stabilizing effect on the MSD1 domain in the region of the N-terminus of the CFTR protein. Ivacaftor on the other hand influences the ATP dependent dimerisation/separation of the NBD domain and with that the gating function of CFTR. To give information about further details on the CFTR function does not seem to be sensible to me, as long as the background and aim of the question have not been concretized.

Yours sincerely,
Michael Hogardt

06.05.2015