Two Potentiator Drugs Act on CFTR Protein in Cystic Fibrosis by Holding Hinge Open to Allow Ion Flow; Focus on This Mechanism May Enable Further Progress on Drug Development & Disease Treatment

In recent decades, treatment options for people with cystic fibrosis have improved dramatically. The newest drugs, known as potentiators, target a protein called cystic fibrosis transmembrane conductance regulator (image), which is mutated in people with the disease. Yet, while these medications can help some people with CF, they are far from perfect. Moreover, researchers haven't been able to figure out how the drugs actually work--until now. A new study by Rockefeller University scientists in New York characterizes, for the first time, the interaction between potentiators and the protein they target at atomic resolution. The research, described in a report in the June 21, 2019 issue of Science, shows that two distinct compounds act on the same protein region--a finding that points to strategies for developing more effective drugs. The article is titled “Structural Identification of a Hotspot on CFTR for Potentiation.” The cystic fibrosis transmembrane conductance regulator (CFTR) is a channel that, when open, allows chloride ions to move in and out of cells. When CFTR is mutated, ions cannot flow freely, leading to changes in the make-up of mucus lining internal organs. These changes can be particularly dangerous in the lungs where they cause thick mucus to accumulate, often leading to impaired breathing and persistent infections. Potentiators are used to increase the flow of ions through CFTR, ameliorating some symptoms of cystic fibrosis (CF). Currently, only one such drug, known as ivacaftor, is on the market; another, called GLPG1837, is now in development. "Ivacaftor can improve lung function by about ten percent. It can help a lot, but it's not a cure and not everybody responds to it," says Jue Chen, PhD, the William E. Ford Professor at Rockfeller.
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