|
E-mail this page to a friend!
Alzheimers Drug May Come from Discovery of
Molecules
July 23, 2005 - A team of scientists has discovered
three molecules from a search of 58,000 compounds that appear to
inhibit a key perpetrator of Alzheimer's disease. Each of the three
molecules protects the protein called "tau," which becomes hopelessly
tangled in the brains of patients with Alzheimer's. The finding is
promising news for the development of drugs for the disease.
Ken Kosik, co-director of the Neuroscience Research
Institute at the University of California, Santa Barbara, headed the
effort to find these molecules. The results of the study are published
in the July issue of the journal Chemistry and Biology, released on
Friday, July 22.
As baby boomers grow older, the incidence of
Alzheimer's, already increasing, will rise much more. "Our approaches to
the disease are flagrantly inadequate," said Kosik.
"There are a couple of FDA-approved drugs that help
a little, but don't modify the disease. They give a little bit of
symptomatic relief, but don't change the inexorable progression of the
disease."
He said that new insights made over the past decade
help to understand the molecular and genetic basis of the disease and
these can now be built upon for the development of treatments. "There is
no doubt that we need new approaches," said Kosik. "The insights gained
about the mechanisms of the molecular and genetic basis of the disease
are beginning to add up and can be harnessed for treatments."
Alzheimer's involves a complicated, interwoven
series of regulatory steps of genes and proteins "talking" to each
other, he explained. "When the conversation goes awry the disease
process begins. And it is not just one gene or one protein causing the
damage."
The complexity of Alzheimer's means that several
different medications will likely be needed to control it, said Kosik.
The same is true for many other diseases from AIDS to cancer. "It is
likely that we will need to strategically target different aspects of
the disease and put them together."
Kosik and his team chose to focus on the
neurofibrillary tangles of neurons in the brain that, along with senile
plaques, characterize Alzheimer's disease. The tangles are made of "tau,"
a protein that is also present normally in the brain.
"Tau goes wrong and becomes pathological when it
becomes intensely phosphorylated," said Kosik. "This means that many
phosphate groups attach to tau--modify it--and cause it to become
dysfunctional."
The culprit is an enzyme, called CDK5, that
attaches the phosphate to the tau protein, facilitating the disease
process. The researchers set out to find a way to inhibit this enzyme,
to keep it from putting any phosphate on tau.
In the laboratory, they purified the enzyme and
purified tau protein, and watched tau get phosphorylated by the enzyme.
They then performed a library search of small molecules (58,000 of them)
in an attempt to find those that would prevent phosphorylation. Small
molecules are preferred because they are more easily used as a drug
since they can get through the body and into cells. It is also important
to find molecules that will cross the blood brain barrier.
They then set up a test of nearly 400 small
molecules that fit their criteria. The test results showed three small
molecules that can inhibit the enzyme. These are candidates for
development as drugs.
Kosik explained that proteins are strings of amino
acids folded into small globs. All proteins that happen to be an enzyme
involved in phosphorylation have one thing in common. They have a pocket
that is almost always in the same place and this is where the phosphate
attaches to the enzyme, in this case CDK5. To get a molecule that
specifically prevents the enzyme from binding at the pocket is
difficult.
Of the three compounds that the research group
found, the scientists were able to locate where they bind. They found
that one binds in the pocket, another binds at the edge of the pocket,
and a third appears to bind completely outside the pocket. The
scientists are most interested in the second and third compounds.
"This is the first demonstration that we can find
small molecules that can more specifically affect the phosphorylation of
tau by CDK5," said Kosik.
In terms of future directions, Kosik said, "There
is lots to do here, lab testing, testing in animals, etc. But we have
made an important step forward toward developing treatments for this
disease."
He noted that this work is of a type usually
performed by pharmaceutical companies, but in this case was completed in
an academic environment.
About the study
The work was partly funded by NIH grants, the
Institute for the Study of Aging, and the Department of Energy
Computational Science Graduate Fellowship.
In addition to Kosik, authors of the paper include:
Jae Suk Ahn, Sungwoon Choi, and Gregory D. Cuny of the Department of
Neurology and Laboratory for Drug Discovery in Neuroegeneration of
Brigham and Women's Hospital, Harvard Medical School; Mala L.
Radhakrishnan of the Computer Science and Artificial Intelligence
Laboratory, Department of Chemistry, Massachusetts Institute of
Technology; Marina Mapelli and Andrea Musacchio of the Structural
Biology Unit of the Department of Experimental Oncology, European
Institute of Oncology, Milan, Italy; Bruce Tidor of the Computer Science
and Artificial Intelligence Laboratory, Biological Engineering Division,
Department of Electrical Engineering and Computer Science, Massachusetts
Institute of Technology.
Click to More Senior News on the
Front Page
Copyright: SeniorJournal.com |
