Drug Discovery and Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Voices
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE

A possible fix for misfolding proteins

By Drug Discovery Trends Editor | June 23, 2011

/sites/rdmag.com/files/legacyimages/RD/News/2011/06/Gaucher_graphicx500.jpg

click to enlarge

A new study by Rice Univ. researchers shows small molecules that function as calcium blockers, particularly ryanodine and lacidipine, enhance a cell’s protein-folding capacity by restoring calcium homeostasis. They found calcium imbalance leads to misfolding of glucocerebrosidase (GC), which in turn causes an aberrant accumulation of lipids, the root of Gaucher disease. Calcium is regulated by ryanodine (RyaR) and inositol (InsP3) receptors and SERCA pumps on the cell’s endoplasmic reticulum (ER). Source: Segatori Lab/Rice Univ.

Troubled proteins in need of rescue may someday have a champion in a common
drug used to treat high blood pressure.

The Rice Univ. laboratory of bioengineer Laura Segatori reported that
research involving lacidipine, a calcium channel blocker also known by brand
names Lacipil and Motens, could be a key to helping people who suffer from an
incurable, neuropathic form of Gaucher disease. This inherited metabolic
disorder is characterized by accumulations of a fatty substance in cells and
certain organs that can prevent them from functioning properly.

The paper by Segatori, Rice’s T.N. Law Assistant Professor in Chemical and
Biomolecular Engineering, and graduate student Fan Wang and Rice senior Ann
Chou appears in Chemistry
and Biology
.

Segatori’s research focuses on the misfolding of proteins. Proteins start as
chains of amino acids that snap in an instant into distinct configurations, a
process that remains one of biology’s great mysteries but one that Segatori and
her peers are figuring out, bit by bit.

Proteins often misfold even in the healthiest persons, Segatori said, and
cells have an elegant, efficient system for eliminating misfolded proteins and
other refuse. But the system can break down.

In Gaucher disease, proteins containing destabilizing mutations misfold and
are degraded very quickly. Loss of these proteins, which normally traffic to
the lysosome and catalyze the degradation of lipids, results in buildup of
these lipids; this can lead to such problems as a malfunctioning liver,
enlarged spleen, skeletal disorders, anemia, and neurological disorders.

The Rice researchers worked with fibroblasts taken from skin lesions of
people with Gaucher. They found that lacidipine enhances the protein-folding
mechanism by modulating calcium levels and regulating the movement of signaling
calcium ions.

Segatori said impairment of calcium homeostasis further compromises the
folding of already destabilized, mutated versions of the enzyme glucocerebrosidase
(GC). Slowing the folding process ever so slightly by regulating calcium
stabilizes GC and lets it fold properly and enter the lysosome, where it breaks
down lipids.

“If you can force the folding to occur, you can rescue native folding
of mutant proteins, which has been shown to lead to restored activity,”
Segatori said.

Segatori and Wang hope their work opens the door to possible treatments for
neuropathic diseases that will be easier on patients and less expensive than
enzyme replacement therapy, which involves injecting recombinant protein.
Segatori said lacidipine has three distinct advantages: It is nontoxic to
cells, is a small molecule that readily crosses the blood/brain barrier and is
approved for use in humans by the Food and Drug Administration.

On the other hand, the researchers have not yet studied the effect of
lacidipine on neurons. “We don’t want to say we can cure this disease with
calcium blockers, but they are a good tool for research,” Segatori said.
“Essentially, we treat cells with this molecule and see if we rescued the
protein activity. If we did, we can then work to understand what the molecule
actually did to the folding machinery of the cell.”

She also cautioned that calcium blockers might have side effects.
“Their response in the cell is quite broad. That’s why I’m hesitant to say
that this could be a cure for Gaucher disease. Maybe we’re rescuing the folding
of that enzyme, but we don’t know what else we might be doing.”

But the positive implications go beyond Gaucher. “There is possibly an
avenue to use calcium blockers to further the study and treatment of other
types of misfolding diseases,” Segatori said. “Similar studies have
been conducted using calcium blockers in neurons of Parkinson’s patients. The
results are highly promising. And there’s also a lot of interest in the
correlation between Parkinson’s and Gaucher diseases, because it seems like a
lot of people who have Gaucher are at risk for Parkinson’s disease.”

SOURCE


Filed Under: Drug Discovery

 

Related Articles Read More >

Sanders, King target DTC pharma ads but the industry worries more about threats to its $2B R&D model
Zoliflodacin wins FDA nod for treatment of gonorrhea
FDA approved ENFLONSIA for the prevention of RSV in Infants
First clinical study results of Dupixent for atopic dermatitis in patients with darker skin tones 
“ddd
EXPAND YOUR KNOWLEDGE AND STAY CONNECTED
Get the latest news and trends happening now in the drug discovery and development industry.

MEDTECH 100 INDEX

Medtech 100 logo
Market Summary > Current Price
The MedTech 100 is a financial index calculated using the BIG100 companies covered in Medical Design and Outsourcing.
Drug Discovery and Development
  • MassDevice
  • DeviceTalks
  • Medtech100 Index
  • Medical Design Sourcing
  • Medical Design & Outsourcing
  • Medical Tubing + Extrusion
  • Subscribe to our E-Newsletter
  • Contact Us
  • About Us
  • R&D World
  • Drug Delivery Business News
  • Pharmaceutical Processing World

Copyright © 2025 WTWH Media LLC. All Rights Reserved. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of WTWH Media
Privacy Policy | Advertising | About Us

Search Drug Discovery & Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Voices
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE