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Discovery could increase efficacy of promising cystic fibrosis drug
Date:3/21/2013

very of our recent papers summarized in Physiology."

Like an automatic water faucet with a defective hand sensor, many genetic mutations found in cystic fibrosis patients cause a faulty signal, resulting in limited chloride transport across the CFTR. The result is the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body, which leads to severe respiratory and digestive problems, as well as infections and diabetes.

As summarized in Physiology and followed up with further research in the PNAS article, the accidental discovery of a mutation in CFTR, the R532 mutation, allowed MU researchers to reveal a new "non-strict coupling" relationship that occurs between the consumption of ATP, a molecule that provides energy in the body, and the opening and closing of the CFTR. They argue that the new information uncovered about this mechanism that controls the opening and closing of the CFTR and the passage of ions through it could explain how and where the new cystic fibrosis treatment Kalydeco (Vx-770) works.

"To his credit, Dr. Hwang exploited the behavior of the CFTR mutants to demonstrate that CFTR's gate is not strictly coupled to the nucleotide binding engine (NBD) that binds and splits ATP [energy] to drive conformational changes that regulate chloride flow through the CFTR protein channel," said colleague David Sheppard, PhD, an associate professor in the School of Physiology and Pharmacology at the University of Bristol in Bristol, U.K. who did not participate in the study.

In their study, MU researchers were able to observe the effects of the cystic fibrosis drug Vx-770 on the recently discovered R352 mutation. They found that Vx-770 enhances the activity of the CFTR channel by exploiting this "non-coupling" mechanism, a conclusion also supported by experimental results with the wild-type CFTR protein.

"Traditionally, researchers have defined how energy is utilized and transferre
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Contact: Michael Muin
muinm@health.missouri.edu
573-884-7541
University of Missouri School of Medicine
Source:Eurekalert  

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