A New Therapy for a Rare Form of Cystic Fibrosis
Scientists at the Hospital for Sick Children in Toronto have established that a drug recently approved by the U.S. Food and Drug Administration to treat a rare form of cystic fibrosis works in an unconventional way. Their results reveal new possibilities for treating more forms of cystic fibrosis
by Danielle Gutierrez
Cystic fibrosis is an inherited disease afflicting about 70,000 people around the world. Patients carry a defective gene that disables or destroys its protein product, which normally regulates the transport of ions across cell borders. When that transport is disrupted, the viscosity of the mucus coating certain organs becomes too thick. A characteristic feature of the disease is thick mucus buildup in the air passages, which causes difficulty breathing and recurring infections.
While the FDA approved the drug VX-770
(also known by the trade names Kalydeco and Ivacaftor)
to ease breathing in people with cystic fibrosis
caused by a particular mutation in the CFTR
protein (the acronym is short for cystic fibrosis
transmembrane conductance regulator),
exactly how VX-770 worked in
those patients was unknown.
Scientists have understood for some time that normal CFTR regulation requires modification of the protein and binding of a small, energy-providing molecule adenosine triphosphate, or ATP. But, in their recent Journal of Biological Chemistry "Paper of the Week," Christine Bear and colleagues report that the drug opens both normal and mutant CFTR channels without ATP.
The results indicate that the compound
binds to a different site on CTFR than ATP.
Significantly, this finding may be useful in
developing therapies for cystic fibrosis caused
by various CFTR mutations that,
like the G551D mutation that was studied,
impair ATP-mediated channel regulation.
Bear's group determined how VX-770 works after developing a new experimental system that may have potential for discovering drugs that target the basic defects caused by CFTR mutations. Bear says the system is useful for identifying compounds that interact with rare mutations such as G551D as well as the major CFTR mutant F508del.
From the article: "CFTR potentiator VX-770 (Ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner" by Paul D.W. Eckford, Canhui Li, Mohabir Ramjeesingh and Christine E. Bear.
Corresponding author: Christine E. Bear, Programme of Molecular Structure & Function, Research Institute, Hospital for Sick Children, in Toronto, Ontario, Canada; email: email@example.com.
The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.
Original article: http://www.eurekalert.org/pub_releases/2012-10/asfb-iia102612.php