The surface of
cells and many biologically active molecules are studded with sugar structures
that are not used to store energy, but rather are involved in communication,
immunity, and inflammation. In a similar manner, sugars attached to drugs can
enhance, change, or neutralize their effects, says Jon Thorson, a professor of pharmaceutical sciences at the University of
Wisconsin-Madison School of Pharmacy.
Thorson, an
expert in the attachment and function of these sugars, says that understanding
and controlling them has major potential for improving drugs, but that
researchers have been stymied because many novel sugars are difficult to create
and manipulate. “The chemistry of these sugars is difficult, so we have
been working on methods to make it more user friendly,” he says.
Now, in a study
published online in Nature
Chemical Biology, Thorson, graduate student Richard Gantt,
and postdoctoral fellow Pauline Peltier-Pain have described a simple process to
separate the sugars from a carrier molecule, then attach them to a drug or
other chemical. The process also causes a color change only among those
molecules that have accepted the sugar. The change in color should support a
screening system that would easily select out transformed molecules for further
testing. “One can put 1,000 drug varieties on a plate and tell by color
how many of them have received the added sugar,” Thorson says.
Attached sugars
play a key role in pharmacy, says Thorson. Not only can they change the
solubility of a compound, but “there are transporters in the body that
specifically recognize certain sugars, and pharmaceutical companies have taken
advantage of this to direct molecules toward specific tissue or cell types. If
we can build a toolbox that allows us to make these molecules on demand, we can
ask, ‘What will sugar A do when it’s attached to drug B?'”
And although the
new study was focused more on an improved technique rather than the alteration
of drugs, Thorson adds that it does describe the production of some
“really interesting sugar-appended drugs: anti-virals, antibiotics,
anti-cancer, and anti-inflammatory drugs. Follow-up studies are currently under
way to explore the potential of these analogs.”
The new
molecules included 11 variants of vancomycin, a powerful antibiotic, each
distinguished by the nature and number of attached sugars.
The essence of
the new process is its starting point: a molecule that changes the energy
dynamics of the sugar-attachment reaction, Thorson says. “This is one of
the first systematic studies of the equilibrium of the reaction, and it shows
we can drive it forward or in reverse, depending on the molecule that we start
with.”
In a single test
tube, the new technique is able to detach the sugar from its carrier and
reattach it to the biological target molecule, Thorson says. “Sugars are
involved a vast range of biology, but there are still many aspects that are not
well understood about the impact of attaching and removing sugars, partly because
of the difficulty of analyzing and accessing these species.”
Making variants
of potential and existing drugs is a standard practice for drug-makers, and a
recently published study by Peltier-Pain and Thorson revealed that attaching a
certain sugar to the anti-coagulant Warfarin destroys its anti-clotting
ability. The transformed molecule, however, “suddenly becomes quite
cytotoxic—it kills cells,” he says. “We don’t know the mechanism, but
there is some interest in using it to fight cancer because it seems to act
specifically on certain cells.”
Sugars are also
attached to proteins, cell surfaces, and many other locations in biology,
Thorson says. “By simplifying the attachment, we are improving the
pharmacologist’s toolbox. This study provides access to new reagents and offers
a very convenient screening for new catalysts and/or new drugs, and for other
things we haven’t yet thought of. We believe this is going to open up a lot of
doors.”
Filed Under: Drug Discovery
