Scientists at The Scripps Research Institute (TSRI) have created a synthetic molecule that mimics “good” cholesterol and have shown it can reduce plaque buildup in the arteries of animal models. The molecule, taken orally, improved cholesterol in just two weeks.
This research, published in the October issue of Journal of
Lipid Research, points scientists toward a new method for treating
atherosclerosis, a condition where plaque buildup in the arteries can cause
heart attacks and strokes.
"Atherosclerosis is the number one
killer in the developed world,” said TSRI Professor M. Reza Ghadiri, senior
author of the new study with TSRI Assistant Professor of Chemistry Luke Leman.
"This research clears a big step toward clinical implementation of new
therapies.”
Good Versus Bad Cholesterol
To combat atherosclerosis, researchers are looking for new
ways to target and remove low-density lipoprotein (LDL) cholesterol (commonly
known as "bad” cholesterol) from the body. Though the body needs some LDL to
stay healthy, high levels lead to dangerous plaque buildups. In contrast,
high-density lipoprotein (HDL) cholesterol ("good” cholesterol) is known for
its protective effects.
"HDL is like a taxi in the
bloodstream; it takes the LDL cholesterol out of the blood and delivers it to
the liver,” said Yannan Zhao, a postdoctoral researcher in Ghadiri’s lab and
first author of the new study. From the liver, the LDL is packaged for elimination
from the body.
Using a method reported by the researchers last year in the
Journal of the American Chemical Society, the team created a "nanopeptide” to
have three arm-like structures that can wrap around cholesterol and fats in the
blood.
Once the synthetic peptide wraps around LDL cholesterol, it
removes it by mimicking the behavior of apoA-1, a protein of HDL, and carrying
it to the liver for elimination.
A Surprising Finding
In collaboration with Linda Curtiss, formerly a faculty
member at TSRI, and Bruce Maryanoff, formerly at Johnson & Johnson and
currently a visiting scholar at TSRI, the researchers tested this synthetic
peptide in a mouse model prone to atherosclerosis.
The team originally used the synthetic peptide in an
experiment the researchers thought was a gamble. They gave it to mice in their
drinking water, but assumed their digestive acids might break down the peptide
before it got a chance to interact with its target and modify LDL cholesterol.
To their surprise, it worked.
After 10 weeks of treatment, the mice had a 40 percent
reduction in potentially harmful cholesterol in their blood and a 50 percent
reduction in the size of plaque lesions in their hearts.
"We were definitely surprised at the
results in the oral feeding studies,” said Leman. "We’ve repeated it many times.”
Many cholesterol treatments currently in development rely on
an injection, not a pill. With the option of an orally effective peptide,
Ghadiri believes researchers are closer to developing an accessible new therapy
for atherosclerosis.
The researchers also reported no signs of increased
inflammation in the blood or toxicity after 10 weeks of the peptide treatment.
Future Studies Point to Gut
Ghadiri and his team are now investigating exactly how the
synthetic peptide works in the intestines and the possibility that it interacts
with beneficial microbes. The researchers believe that finding new targets in
the gastrointestinal tract could lead to new therapies for many more diseases.
"That’s one of the fun things in
science—now we get to follow up on these different avenues,” said Leman.
In addition to Ghadiri, Leman, Zhao, Curtiss and Maryanoff,
other contributors to the study, "In vivo efficacy of HDL-like nanolipid
particles containing multivalent peptide mimetics of apolipoprotein A-1,” are
Audrey S. Black and David J. Bonnet of TSRI.