Insights into a cystic fibrosis treatment may herald a novel class of
drugs

Date:
January 24, 2022
Source:
Rockefeller University
Summary:
Protein folding diseases, from Alzheimer's to Gaucher's, may one
day be treated by a unique class of protein corrector molecules
that are already helping manage cystic fibrosis.



FULL STORY ========================================================================== Protein misfolding is a likely culprit in many degenerative
disorders. Cystic fibrosis, for instance, is caused by mutations in the
CFTR gene that prevent the eponymous protein from assuming its proper configuration. Mutations that impair how other proteins fold have been
linked to Alzheimer's, Parkinson's, and Huntington's disease.


==========================================================================
Now, a new study demonstrates that drugs commonly used to treat cystic
fibrosis work by directly aiding the protein folding process -- binding
CFTR to ensure that the protein has ample time to bend into shape. The findings, published in Cell, may serve as a roadmap for the development of future medications to treat other diseases caused by misfolded proteins.

"Knowing how these drugs bind the protein enabled us to build a theory
of how protein folding correctors work at a fundamental level," says
first author Karol Fiedorczuk, a postdoc in the laboratory of Jue
Chen at The Rockefeller University. "When analyzing the structure of
a protein bound to a drug, we can usually see just a snapshot of the interaction. However, the structural information we obtained in this
study reveals a thermodynamic theory of how the correctors improve the
process of CFTR folding." A problem protein It was not until about
two decades ago that effective treatments for cystic fibrosis became
available. Before that, patients seldom lived past age 30. Many now live
well into their 50s.

Scientists understood the contours of the disease well enough. At the
heart of this genetic condition is CFTR, a protein channel that sits on
the surface of cells lining the lungs and digestive tract. By spitting out chloride ions, the channel attracts water that thins mucus and prevents
it from accumulating.



==========================================================================
If the protein doesn't fold correctly, it breaks down inside the cell and
never reaches the surface. As a result, mucus accumulates and hardens,
making it difficult to breathe and digest. And pathogens caught in the
mucus stick around longer, causing frequent infections. Lung disease,
GI problems, and infections are therefore common symptoms of cystic
fibrosis, along with malnutrition, kidney disease, and infertility.

Even in healthy people, CFTR is prone to misfolding and may degrade
before it can do its job (although enough of the protein remains to keep
the body healthy). Cystic fibrosis mutations exacerbate the problem,
rendering the already-temperamental protein even more unstable.

"When patients have a mutation in the CFTR gene, little or none of the
protein reaches the cell's surface, or those proteins that do reach the
surface function inefficiently," Chen says.

Nestling into notches Researchers have long known that CFTR malfunction
was the root cause of cystic fibrosis. But no treatment appeared to be forthcoming until a massive screening effort yielded two classes of
drugs that, fortuitously, made it possible to manage the symptoms of
the disease.



==========================================================================
It was initially unclear how either medication worked, although both were undeniably effective. In 2019, Chen's lab finally described the mechanism
by which the first class of drug, known as potentiators, props open the
CFTR channel, ensuring that whatever proteins manage to reach the cell
surface can efficiently export chloride and attract water.

But the workings of the second type of drug, known as correctors, left researchers scratching their heads. Some suspected that correctors
somehow helped proteins to fold properly in the first place, ensuring
that they make it to the cell's surface. "But how that small molecule
helped CFTR fold was completely unknown," Chen says. "There were all
kinds of theories." Chen and Fiedorczuk have now solved this puzzle,
with the help of cryo-electron microscopy. Thousands of snapshots of
the drug in action demonstrated that correctors stabilize CFTR in its
earliest stages of biogenesis, nestling into a notch within the protein
and holding it in place. This prevents it from degrading prematurely,
granting it time to finish folding.

The findings could have wide-ranging implications, enabling the
development of novel drugs for a spectrum of illnesses linked to improper protein folding.

"CFTR is not the only protein that folds incorrectly,"
Chen says. "Hundreds of diseases are caused by proteins
failing to form the correct 3D structure. We now have a way
to identify molecules that may be used to treat these diseases." ========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Karol Fiedorczuk, Jue Chen. Mechanism of CFTR correction by type I
folding correctors. Cell, 2022; 185 (1): 158 DOI: 10.1016/
j.cell.2021.12.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220124115056.htm

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