Scientists exploring new compounds to target muscular dystrophy

Scientists have identified a promising set of new compounds in the fight against muscular dystrophy.

Using
a drug-discovery technique in which molecules compete against each
other for access to the target ““ the strand of toxic RNA that causes
the most common form of muscular dystrophy in adults ““ a team at the
University of Rochester Medical Center has identified several compounds
that, in the laboratory, block the unwanted coupling of two molecules
that is at the root of the disease.

The work was published online November 7 by the Journal of the American Chemical Society.

"This
discovery gives us, for the first time, a molecule that targets the
wayward RNA at the root of myotonic muscular dystrophy," said Benjamin
Miller, Ph.D., the chemist who led the study. "This is a first step
toward developing a drug-like molecule that perhaps could be used
someday to treat the disease. This lead molecule provides a framework
for moving forward."

Miller leads a team that is developing
small molecules that target small strands of RNA. He notes that drugs
more commonly target proteins or DNA, but that RNA offers an alluring
target for some diseases.

"The drug discovery field really is
wide open when it comes to RNA, which is a very difficult molecule to
target," said Miller, who is an associate professor in the departments
of Dermatology, Biomedical Engineering, and Biochemistry and Biophysics.

The
work is the latest in a series of developments in which a Rochester
team led by neurologist Charles Thornton, M.D., has shown how a genetic
flaw creates the symptoms of myotonic dystrophy, which affects about
35,000 Americans.

"This is an important first step toward
developing a drug treatment for myotonic dystrophy. The message from
our patients is loud and clear ““ push this forward as fast as
possible," said Thornton, who is co-director of University’s
Neuromuscular Disease Center.

The disease is marked by
progressive muscle weakness, and eventually many patients have
difficulty walking, swallowing, and breathing. The disease also affects
the eyes, the heart, and the brain. Currently there is no treatment.

The
genetic mistake involves a repeated sequence of three chemical bases.
Healthy people have anywhere from five to 30 copies of the "triplet
repeat" known as CUG on chromosome 19, but people with the disease
typically have hundreds or thousands of copies, a kind of molecular
stutter. These extra copies become part of large, faulty messenger RNA
molecules that can mistakenly glom onto proteins and knockout their
normal function.

Earlier this decade, Thornton’s team
discovered that the faulty messenger RNA has a toxic effect on muscle
and heart tissue. The team found that the toxic RNA binds tightly to a
crucial protein known as "muscle blind" or MBNL1 and prevents that
protein from performing its usual function, ultimately leading to the
muscle symptoms of muscular dystrophy.

The goal for doctors is
to free up MBNL1 in cells so that it can go about its normal
activities, which include building proper chloride channels that are
central to normal muscle function.

So Miller set out to free
MBNL1 by designing an experiment to search for a small molecule that
would sop up extra CUG copies. Using a technique known as dynamic
combinatorial chemistry, Miller mixed two sets of 150 compounds, one on
polymer beads and the other in solution, and let the components link up
with each other in a kind of molecular dance, amid a sea of CUG
"triplet repeat" RNA strands. The technique, which Miller helped to
pioneer more than a decade ago, allowed him to simultaneously analyze
how effectively more than 11,000 molecular combinations could bind to
the target CUG RNA strand.

Miller’s team sorted out which
combinations muscled out the others for access to RNA strands and held
most tightly onto them. The team then took the best performers and put
them in a solution containing both CUG repeat RNA and MBNL1. Miller’s
molecules were able to break up the interaction between the two, with
the best molecules freeing up to half the MBNL1 ““ the precise step that
needs to be taken in patients with the disease.

The team is
continuing its work, further refining the molecules in an attempt to
find one that frees MBNL1 even more effectively.

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