An abnormal protein, left, is intercepted by the UW’s compound
that can bind to the toxic protein and neutralize it, as shown
July 28, 2014 -There is no cure for Alzheimer’s disease and other forms of
dementia, but University of Washington bioengineers are one step closer
to finding a treatment. They have designed a peptide structure that can
stop the harmful changes of the body’s normal proteins into a state
that’s linked to widespread diseases such as Alzheimer’s, Parkinson’s,
heart disease, Type 2 diabetes and Lou Gehrig’s disease.
The synthetic molecule blocks these proteins as
they shift from their normal state into an abnormally folded form by
targeting a toxic intermediate phase.
The discovery of a protein blocker could lead to
ways to diagnose and even treat a large swath of diseases that are hard
to pin down and rarely have a cure.
“If you can truly catch and neutralize the toxic
version of these proteins, then you hopefully never get any further
damage in the body,” said senior author
Valerie Daggett, a
UW professor of bioengineering.
“What’s critical with this and what has never been
done before is that a single peptide sequence will work against the
toxic versions of a number of different amyloid proteins and peptides,
regardless of their amino acid sequence or the normal 3-D structures.”
published online this month in the journal
More than 40 illnesses known as
amyloid diseases –
Alzheimer’s, Parkinson’s and rheumatoid arthritis are a few – are linked
to the buildup of proteins after they have transformed from their
normally folded, biologically active forms to abnormally folded, grouped
deposits called fibrils or plaques. This happens naturally as we age, to
a certain extent – our bodies don’t break down proteins as quickly as
they should, causing higher concentrations in some parts of the body.
Each amyloid disease has a unique, abnormally
folded protein or peptide structure, but often such diseases are
misdiagnosed because symptoms can be similar and pinpointing which
protein is present usually isn’t done until after death, in an autopsy.
As a result, many dementias are broadly diagnosed
as Alzheimer’s disease without definitive proof, and other diseases can
go undiagnosed and untreated.
The molecular structure of an amyloid protein can
be only slightly different from a normal protein and can transform to a
toxic state fairly easily, which is why amyloid diseases are so
prevalent. The researchers built a protein structure, called “alpha
sheet,” that complements the toxic structure of amyloid proteins that
they discovered in computer simulations. The alpha sheet effectively
attacks the toxic middle state the protein goes through as it
transitions from normal to abnormal.
In this diagram, a normal protein begins to convert into a
toxic, intermediate state (above center). The UW’s compound
can bind with the toxic species and neutralize it (below
center), preventing amyloid fibrils from forming.
The structures could be tailored even further to
bind specifically with the proteins in certain diseases, which could be
useful for specific therapies.
The researchers hope their designed compounds could
be used as diagnostics for amyloid diseases and as drugs to treat the
diseases or at least slow progression.
“For example, patients could have a broad
first-pass test done to see if they have an amyloid disease and then
drill down further to determine which proteins are present to identify
the specific disease,” Daggett said.
Working with the UW’s
Center for Commercialization,
they have a patent on one compound and have submitted an application to
patent the entire class of related compounds.
This research began a decade ago in Daggett’s lab
when a former graduate student, Roger Armen, first discovered this new
secondary structure through computer simulations. Daggett’s team was
able to prove its validity in recent years by designing stable compounds
and testing their ability to bind toxic versions of different amyloid
proteins in the lab.
The research was funded by the National Institutes
of Health (General Medicine Sciences), the National Science Foundation,
the Wallace H. Coulter Foundation and Coins for Alzheimer’s Research
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