ScienceDaily (Mar. 26, 2012) — The traditional way of making medicines from
ingredients mixed together in a factory may be joined by a new approach in
which doctors administer the ingredients for a medicine separately to patients,
and the ingredients combine to produce the medicine inside patients' bodies.
That's one promise from an emerging
new field of chemistry, according to the scientist who founded it barely a
decade ago. Carolyn Bertozzi, Ph.D., spoke on the topic -- bioorthogonal
chemistry -- in San Diego on March 27 in delivering the latest Kavli Foundation
Innovations in Chemistry Lecture at the 243rd National Meeting & Exposition
of the American Chemical Society (ACS).
Bertozzi explained that the
techniques of bioorthogonal chemistry may fundamentally change the nature of
drug development and diagnosis of disease, so that the active ingredients for
medicines and substances to image diseased tissue are produced inside patients.
"Suppose a drug doesn't reach
diseased tissue in concentrations high enough to work," Bertozzi said,
citing one example of the potential of the new chemistry. "Maybe it is an
oral drug that doesn't get absorbed very well into the blood through the
stomach. You can imagine a scenario in which doctors administer two parts of
the molecule that makes up the drug. The two units reach diseased tissue in
large amounts or get absorbed through the stomach just fine. Then they
recombine, producing the actual drug in the patient's body. Bioorthogonal
chemistry is chemistry for life…literally!"
Bertozzi explained that
bioorthogonal chemistry opens the door to creating new proteins, fats and
sugars directly inside living cells without harming them. The field emerged
from her frustration in the late 1990s with the lack of tools available to see
sugars on the surfaces of living cells. Chains of these sugars, called glycans,
sit on the surfaces of cells in the body and control the doorways through which
different molecules enter. When a disease-causing virus enters and infects a
cell, for instance, proteins on the virus's surface attach to certain glycans.
"To do that, we had to come up
with a chemical reaction that would be really selective, only targeting the
sugar of interest and the fluorescent probes that we delivered to it,"
said Bertozzi. The chemicals also couldn't stick to other biomolecules that the
researchers didn't want to see.
That turned out to be a tall order,
indeed. "We pulled all of our big textbooks off the shelves and flipped
through them to see if there was something out there that fit our
criteria," she said. Those criteria were essentially the conditions inside
a living cell or living organism such as a mouse -- a reaction that could occur
in water at pH 7 and at 98.6 degrees Fahrenheit. The reaction also couldn't
interfere with all the other biomolecules in a cell or organism that keep it
alive.
"It was a pretty restrictive
set of conditions that a traditionally trained organic chemist like me never
had to work within," she explained. That's because these types of
reactions are usually performed in very clean, dry test tubes and flasks under
conditions that the chemist can control. A living cell or organism, with all
its water, proteins, fats, sugars and metabolites is very messy and
uncontrollable by comparison.
Bertozzi and her team at the
University of California, Berkeley, went on to develop a slew of reactions that
can add fluorescent labels to biomolecules.
Now, the field is exploding, with
her group and others reporting new bioorthogonal chemical reactions every year
that help researchers see sugars, fats, proteins, and even DNA and RNA, that
can't be seen using conventional methods. Researchers currently use the
reactions not only to see where a biomolecule is within a living cell or
organism, but also to determine when a biomolecule is made and what it binds
to. Researchers also are using the methods to add things besides labels, like
drugs, to various biomolecules. Some of the chemicals used for the reactions
are currently available separately or in kits.
Several of Bertozzi's reactions are
patented, and some are licensed to companies, including Redwood Bioscience, a
company she co-founded with David Rabuka, Ph.D. The company is focused on
bringing this technology to the clinic.
The scientists acknowledged funding
from the National Institutes of Health and the Howard Hughes Medical Institute.
