Approved and investigative cystic fibrosis (CF) treatments known as CFTR potentiators work by binding to the same flexible protein spot — a place that acts like a hinge — and keeping it open, according to a study whose findings may lead to more effective therapies.
The research, “Structural identification of a hotspot on CFTR for potentiation,” was published in the journal Science.
CF is caused by mutations in the CFTR gene (standing for cystic fibrosis transmembrane conductance regulator), which impairs ion and water transport across cells. This leads to a buildup of thick mucus in organs that include the lungs, and to persistent infections and difficulties breathing.
The CF treatment ivacaftor — a CFTR potentiator marketed as Kalydeco, and used in Orkambi and Symdeko formulations, all by Vertex Pharmaceuticals — works by improving the flow of chloride through the CFTR protein, and by prolonging the time this channel is open.
However, as ivacaftor only partly improves lung function and not all patients respond to it, a team at The Rockefeller University aimed to better understand how CTFR potentiators work.
“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,” Jue Chen, the study’s senior author, said in a press release. “So there’s a lot of interest in developing new potentiators.”
Using a technique called cryo-electron microscopy — in which a beam of electrons is directed at a frozen sample to reveal protein architecture at an atomic level — the scientists studied the structure of the CFTR protein bound to either ivacaftor or GLPG1837, a potentiator in clinical development (by Galapagos and AbbVie).
Results showed that, although different, the two compounds bind to the exact same spot within the CFTR protein region that spans the cell membrane.
“These compounds are developed by two different companies and have very different chemical properties. But they manage to make their way to the same site,” Chen said. “That tells us that this is a very sensitive, very important region of the protein.”
Investigators then discovered that this key region contains unwound loops that are critical to its function. By inducing mutations at specific amino acids in the CFTR protein, they also found that hydrogen bonds are important for the docking of both ivacaftor and GLPG1837.
“The region we identified,” Chen said, “works as a hinge that swings open to allow ions through the channel — so its structure needs to be flexible.” By binding to that region, ivacaftor and GLPG1837 keep the channel open and improve ion flow. “That’s how they work,” Chen said.
The researchers now aim to use this information to develop compounds that more effectively target the hinge, and maintain the CFTR channel open. “The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds,” they wrote.
Other scientists are welcome to join this effort. “We put our original data online and welcome anyone to use it,” Chen said. “Because if more researchers use it, more treatment options will become available, prices will drop, and more people will be helped.”