X-Message-Number: 29463
Date: Wed, 25 Apr 2007 11:38:25 -0700 (PDT)
From: 
Subject: beta-secretase inhibitors to treat Alzheimer's

[Or just drink pomegranate juice. (see below)]

Research Could Lead To Treatment For Alzheimer's Disease
Science Daily - A molecule designed by a Purdue University researcher
could lead to the first drug treatment for Alzheimer's disease.

Shown is an image of the X-ray crystal structure of the molecule bound to
memapsin 2, the enzyme responsible for amyloid plaque deposits in the
human brain. The bond disables the enzyme and prevents the plaques that
cause Alzheimer's disease. (Credit: Ghosh laboratories)Ads by Google

"There are many people suffering, and no effective treatment is available
to them," said Arun Ghosh, the Purdue professor who designed the
molecule. "There is an urgent need for a drug to treat this devastating
disease, and the scientific community has been working on this problem
for many years."

The National Institute on Aging estimates that as many as 4.5 million
Americans suffer from Alzheimer's disease, which leads to dementia by
affecting parts of the brain that control thought, memory and language.

The new molecule prevents the first step in a chain of events that leads
to amyloid plaque formation in the brain. The material at various stages
of plaque formation is made up of fibrous clumps of toxic proteins that
cause the devastating symptoms of Alzheimer's disease, said Ghosh, who
has a dual appointment in the chemistry and medicinal chemistry and
molecular pharmacology departments.

"Interdisciplinary research and the tools available today allowed us to
build a molecule that is both highly potent and highly selective, meaning
it does not affect other enzymes important to brain function," he said.

Jordan Tang, head of the Protein Studies Research Program at the Oklahoma
Medical Research Foundation, is one of the discoverers of the critical
enzyme and target for intervention, Ghosh said.

Tang discovered a key enzyme called memapsin 2, or beta-secretase, that
is involved in the development of Alzheimer's disease. The action of this
enzyme on a special protein, called the amyloid precursor protein, leads
to the formation of plaques in the brain. The development of an inhibitor
compound targeting memapsin 2 could block this reaction, thus preventing
the disease. Utilizing Tang's information about the enzyme, Ghosh
designed the first memapsin 2 inhibitor.

"This is the most exciting target today for Alzheimer's disease
intervention," said Tang, who holds the J.G. Puterbaugh Chair in Medical
Research at the Oklahoma Medical Research Foundation. "These interactions
happen at a very early stage in the disease, and if we could block them,
we could prevent many of the harmful steps that follow and drastically
reduce the impact. In our most recent tests, a single dose of the
designed compound reduced the beta-amyloid level by 30 percent."

As a therapeutic target, memapsin 2 has an additional advantage because
it belongs to a class of enzymes called aspartyl proteases. Researchers
already have successfully created drugs to block proteases for the
treatment of other diseases. One of these successful drugs was developed
from a molecule designed by Ghosh for treatment of drug-resistant HIV,
which was approved by the Food and Drug Administration last year. The
principles used in the development of these drugs can be carried over and
used in the design of new drugs, Tang said.

Ghosh's team achieved a breakthrough in Alzheimer's disease research when
they were the first to use a method called X-ray crystallography to map
the structure of Ghosh's designed inhibitor bound to the enzyme. This
revealed information necessary to move the research forward and develop
molecules that could be used in drugs.

"The moment we had the crystal structure, we knew exactly how the
inhibitor worked, the interactions of the molecular bonds and what
properties were most important," Ghosh said. "This allowed us to quickly
build inhibitor molecules and bypass the usual lengthy process of trial
and error in molecule design. Within a year we had developed modified
inhibitors that were much smaller and more druglike in character."

Ghosh's most recent research findings and the collaborative research
results with Tang will be published in the May 3 issue of the Journal of
Medicinal Chemistry and are posted on the journal's Web site. Purdue
postdoctoral fellow Nagaswamy Kumaragurubaran and graduate students
Sarang S. Kulkarni and Xiaoming Xu co-authored the paper. In addition, Lin
Hong, Wanpin Chang, Vajira Weerasena, Robert Turner, Gerald Koelsch and
Geoffrey Bilcer from the Oklahoma Medical Research Foundation and
Athenagen Inc. co-authored the paper. The National Institutes of Health
National Institute on Aging funded this research.

"We began this work in 2000 and prepared and examined several hundred
molecules, we now have one with great clinical potential," Ghosh said.

Research into memapsin 2 faced a setback when memapsin 1, an enzyme very
similar in structure, was discovered. Unlike memapsin 2, memapsin1 is
involved in many important biological processes and its inhibition would
cause serious adverse side effects, Ghosh said.

"Unfortunately, all of our early designed compounds that were potent
against memapsin 2 also inhibited memapsin 1," he said. "Selective
inhibition of memapsin 2, or building selectivity, became very
important. The scientific community was faced with a formidable
challenge."

Ghosh's team developed a novel structure-based design strategy to
systematically understand where and how to target memapsin 2
specifically.

"According to our studies, inhibition of memapsin 2 does not cause toxic
side effects," Tang said. "This is extremely encouraging because it
allows for intervention very early in the stages of the disease, and it
is a type of enzyme with which we are very familiar. There is a
precedence of great success in this type of work."

Ghosh and Tang founded the biopharmaceutical company Zapaq, located in
Oklahoma City, which now has merged with CoMentis. San Francisco-based
CoMentis has used the research results of Ghosh and Tang to begin to
develop pharmaceuticals. A drug from the memapsin 2 inhibitor could go
into the first phase of clinical trials this year and begin the lengthy
trial process necessary before the FDA approves a drug to be available on
the market.

Alzheimer's disease usually begins after age 60, and the risk increases
with age. According to the National Institute on Aging, about 5 percent
of men and women ages 65-74 have Alzheimer's disease, and nearly half of
those 85 and older may have the disease.

[Although no effective "drug" treatment for Alzheimer's exists yet,
dietary treatments to achieve this have been available for quite some
time. Doctors will generally not talk about these, because such dietary
items do not generate profit for drug companies. The corporate game has
ALWAYS been not to cure disease, but instead to find ways to make money
treating diseased people. Case in point being pomegranate juice, which
already contains selective inhibitors for beta-secretase. Guess why no
mention is made of this well known fact above.]

Arch Pharm Res. 2005 Dec;28(12):1328-32.
beta-Secretase (BACE1) inhibitors from pomegranate (Punica granatum) husk.
Kwak HM, Jeon SY, Sohng BH, Kim JG, Lee JM, Lee KB, Jeong HH, Hur JM,
Kang YH, Song KS. School of Applied Biosciences, College of Agriculture
and Life Sciences, Kyungpook National University, Daegu, Korea.
    In the course of screening for anti-dementia agents from natural
products, two beta-secretase (BACE1) inhibitors were isolated from the
husk of pomegranate (Punica granatum) by activity-guided
purification. They were identified as ellagic acid and punicalagin with
IC50 values of 3.9 x10(-6) and 4.1x10(-7) M and Ki values of
2.4x10(-5) and 5.9x10(-7) M, respectively. The compounds were
non-competitive inhibitors with a substrate in the Dixon plot. Ellagic
acid and punicalagin were less inhibitory to alpha-secretase (TACE) and
other serine proteases such as chymotrypsin, trypsin, and
elastase, thus indicating that they were relatively specific inhibitors
of BACE1.
PMID: 16392663

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