A hinge-like protein could open the door to a new cure for cystic fibrosis

In recent decades, treatment options for people with cystic fibrosis have improved dramatically. The newest drugs, known as potentiators, target a protein called the cystic fibrosis transmembrane conductance regulator, which is mutated in people with the disease. Yet while these drugs may help some people with CF, they are far from perfect. In addition, researchers have not been able to understand how drugs actually work – until now.

A new study by Rockefeller scientists characterizes, for the first time, the interaction between potentiators and the protein they target at atomic resolution. The research, described in a recent Science report, shows that two separate compounds act on the same protein region – a finding that points to strategies for developing more effective drugs.

Find the hot spot

The transmembrane conductance regulator (CFTR) of cystic fibrosis is a channel that, when open, allows chloride ions to enter and exit cells. When CFTR is mutated, ions can not circulate freely, resulting in changes in the composition of internal mucosal organs. These changes can be particularly dangerous in the lungs where they cause a build up of thick mucus, often leading to breathing problems and persistent infections.

Potentiators are used to increase the flow of ions in the CFTR, thereby attenuating certain symptoms of cystic fibrosis (CF). Currently, only one drug of this type, called ivacaftor, is on the market. another, called GLPG1837, is under development.

"Ivacaftor can improve lung function by about 10% .This can help a lot, but it's not a cure and not everyone responds to it," says Jue Chen, professor at the William E. Ford. "So there is a lot of interest in developing new potentiators."

In pursuit of this goal, Chen and his colleagues studied the workings of existing potentiators. They used cryo-electron microscopy – a technique that radiates electrons on a frozen sample to reveal atomic-level protein architecture – to study the structure of CFTR-related ivacaftor or GLPG1837. Somewhat surprisingly, the researchers discovered that the two drugs bind exactly in the same place on the protein.

"These compounds are developed by two different companies and have very different chemical properties, but they manage to go to the same site," says Chen. "This tells us that it's a very sensitive and very important region of the protein."

Better drugs, more access

After badyzing the "hot spot" where the two potentiators were linked, the researchers noticed a particular characteristic: this area contained loops unwound inside the membrane that signify a flexible structure. And researchers have realized that this flexibility serves a practical purpose.

"It turns out that the region we have identified is functioning as a hinge that opens up to allow ions to cross the channel – so its structure has to be flexible," Chen said. "The compounds we have studied bind to this very region, locking it into an open channel conformation to improve the flow of ions, which is how they work."

With this knowledge, researchers hope to create compounds that directly target the hinge and do even better to keep the ion channel open. And while Chen and her colleagues are developing new drugs, she encourages other researchers to do the same. She hopes that this type of competition will lower the cost of potentiators, allowing more patients to access drugs.

"We put our original data online and invite anyone to use it," said Chen. "Because if more researchers use it, more treatment options will be available, prices will go down and more people will be helped."

Reflecting on this landmark study, Chen salutes the work of David C. Gadsby, who pbaded away in March. Emeritus Professor of the Patrick A. Gerschel family and head of the Cardiac and Membrane Physiology Laboratory, Gadsby's early work on the CFTR laid the groundwork for much of Chen's research.

"He did a series of beautiful functional studies on CFTR and was a source of inspiration and knowledge," she says. "Too bad he did not live to see it, we dedicate this study to him."

Reference: Fangyu Liu, et al. Structural identification of a hot spot on CFTR for potentiation. Science (2019) DOI: 10.1126 / science.aaw7611

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