Scientists Figure Out How Tezacaftor, Lumacaftor Interact With CFTR

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Researchers at The Rockefeller University in New York City have determined how two medications used to treat cystic fibrosis (CF), lumacaftor and tezacaftor, interact with the CFTR protein.

The results suggest that these medicines bind to the protein — usually impaired or missing in people with CF — and help to keep it folded in its correct shape.

“I am … hoping that these data will guide new therapy development to help people who do not respond to current [CF] treatments,” Jue Chen, PhD, an investigator at Rockefeller and co-author of the study, said in a press release.

One scientist not involved in Chen’s research called the discovery “a substantial contribution” in the drive to better understand the mechanisms underlying CF.

“It is groundbreaking for the field,” said Garry Cutting, a medical geneticist at the Johns Hopkins University School of Medicine, in Maryland.

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The findings were published in the study, “Mechanism of CFTR correction by type I folding correctors,” in the journal Cell. The research was done by Chen and Karol Fiedorczuk, a postdoctoral associate at Rockefeller.

CF is caused by mutations in the CFTR gene, which provides cells with instructions for making the CFTR protein. Normally, this protein is present on the surface of cells and acts like a gate, controlling the movements of salts and water in and out of the cell. In CF, however, the protein does not function properly.

A new class of medications, called CFTR modulators, has gained widespread approvals in recent years. These medications broadly can increase the functionality of the CFTR protein in people with specific mutations, helping patients better manage disease symptoms and improving their quality of life.

For example, ivacaftor — sold as Kalydeco by Vertex Pharmaceuticals — is a specific type of CFTR modulator called a potentiator, which works by helping to keep the CFTR protein open on the cellular membrane.

Meanwhile, both lumacaftor and tezacaftor belong to another class of CFTR modulators, called correctors. Lumacaftor is sold in a combination therapy with ivacaftor, called Orkambi, while tezacaftor is part of the dual-combination therapy Symdeko and the triple-combo therapy Trikafta. All of these medications are sold by Vertex.

It has been demonstrated that these treatments can increase the amount of CFTR protein on the cellular surface in people with specific mutations. However, the molecular details of how these molecules interact with the CFTR protein have not been clear.

The typical method that would be used to determine the shape of this interaction is called X-ray crystallography, which involves generating regular protein crystals, with a stable structure, for the analysis. However, because of the particular shape and characteristics of CFTR — it’s too “floppy,” according to the researchers — this protein isn’t well-suited to this method.

“You can’t get a crystal because parts of the protein move a lot,” Chen said.

Instead, the team used a method called cryogenic electron microscopy. This basically involves freezing the proteins at extremely cold temperatures, then taking pictures using powerful microscopes.

The results of these experiments showed that both lumacaftor and tezacaftor bind to the same location on the CFTR protein, a region called the first transmembrane domain or TMD1. Consistently, the team found that mutating the CFTR protein to alter this region reduced the efficacy of these medicines.

A notable conclusion from this finding, the researchers said, is that it implies that these medications work by helping to stabilize the CFTR protein once it is already in its normal shape, rather than binding to misfolded protein and helping it to take on its normal shape.

The finding “provides a structural basis to understand how these compounds promote CFTR folding,” the researchers wrote, adding that “the [CFTR] correctors are able to stabilize the partially folded TMD1 while it awaits the completion of inter-domain assembly.”

The team added that “the location and the chemical nature” of the interactions between these correctors and CFTR “are very different from those of the potentiator ivacaftor,” in that ivacaftor binds to a cleft on a different domain and through chemical interactions of a different type.

Chen said these findings explain how one medication works on patients with different mutations. This knowledge, she said, could help in developing new treatments for people for whom current therapies are not working.

A notable limitation of this study, according to the researchers, is that experiments were done using wild-type CFTR protein, rather than a CF-causing mutant. They also noted that other correctors may not work quite the same way, highlighting a need for further study.

This study was funded by the Howard Hughes Medical Institute and the Cystic Fibrosis Foundation.