SCIENTISTS MAKE DISEASED CELLS SYNTHESIZE THEIR OWN DRUG
In a new study that could ultimately lead to many new medicines, scientists
from the Florida campus of The Scripps Research Institute (TSRI) have adapted a
chemical approach to turn diseased cells into unique manufacturing sites for
molecules that can treat a form of muscular dystrophy.
"We're using a
cell as a reaction vessel and a disease-causing defect as a catalyst to
synthesize a treatment in a diseased cell," said TSRI Professor Matthew
Disney. "Because the treatment is synthesized only in diseased cells, the
compounds could provide highly specific therapeutics that only act when a
disease is present. This means we can potentially treat a host of conditions in
a very selective and precise manner in totally unprecedented ways."
The promising research
was published recently in the international chemistry journal Angewandte
Chemie.
Targeting RNA Repeats
In general, small, low
molecular weight compounds can pass the blood-brain barrier, while larger,
higher weight compounds tend to be more potent. In the new study, however,
small molecules became powerful inhibitors when they bound to targets in cells
expressing an RNA defect, such as those found in myotonic dystrophy.
Myotonic dystrophy
type 2, a relatively mild and uncommon form of the progressive muscle weakening
disease, is caused by a type of RNA defect known as a "tetranucleotide
repeat," in which a series of four nucleotides is repeated more times than
normal in an individual's genetic code. In this case, a
cytosine-cytosine-uracil-guanine (CCUG) repeat binds to the protein MBNL1, rendering
it inactive and resulting in RNA splicing abnormalities that, in turn, results
in the disease.
In the study, a pair
of small molecule "modules" the scientists developed binds to
adjacent parts of the defect in a living cell, bringing these groups close
together. Under these conditions, the adjacent parts reach out to one another
and, as Disney describes it, permanently hold hands. Once that connection is
made, the small molecule binds tightly to the defect, potently reversing
disease defects on a molecular level.
"When these
compounds assemble in the cell, they are 1,000 times more potent than the small
molecule itself and 100 times more potent than our most active lead
compound," said Research Associate Suzanne Rzuczek, the first author of
the study. "This is the first time this has been validated in live
cells."
Click Chemistry
Construction
The basic process used
by Disney and his colleagues is known as "click chemistry" -- a
process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to
quickly produce substances by attaching small units or modules together in much
the same way this occurs naturally.
"In my opinion,
this is one unique and a nearly ideal application of the process Sharpless and
his colleagues first developed," Disney said.
Given the
predictability of the process and the nearly endless combinations, translating
such an approach to cellular systems could be enormously productive, Disney
said. RNAs make ideal targets because they are modular, just like the compounds
for which they provide a molecular template.
Not only that, he
added, but many similar RNAs cause a host of incurable diseases such as ALS
(Lou Gehrig's Disease), Huntington's disease and more than 20 others for which
there are no known cures, making this approach a potential route to develop
lead therapeutics to this large class of debilitating diseases.
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