Antivirals, Anti-Cancers, and Antibiotics in One Pot
By Jason Socrates
Bardi
"Blueberries
as big as the end of your thumb,
Real sky-blue, and heavy, and ready to drum
In the cavernous pail of the first one to come!
And all ripe together, not some of them green
And some of them ripe! You ought to have seen!"
———Robert
Frost, Blueberries, 1915
Panning parts of the chemical universe for compounds that
are active against particular biological targets has been
an established route to drug discovery since the early days
of modern biology. In 1909, for instance, Paul Ehrlich tested
hundreds of chemicals and eventually found one that could
be used to treat syphilis. And Alexander Fleming was searching
for an effective antiseptic when, in 1928, he happened upon
a mysterious bactericidal substance (penicillin) produced
by mold growing in his petri dish.
There is no shortage of human diseases and frailties and
there is no question that these conditions can be treated
or prevented through molecules that, like penicillin, disrupt
some part of the disease process. Molecules on the outside
of cancer cells, for instance, facilitate disease progression
and allow the cells to grow uncontrollably and invade other
tissues.
Viral pathogens like HIV, hepatitis virus, and influenza
use surface molecules to recognize specific cells and invade
the human body. They use other molecules to replicate. The
same is true for bacterial invaders. And if chemicals can
be found to inhibit any of these recognition molecules and
enzymes, then they might make good drug candidates. Now that
the genome has been solved, and as it is annotated, more targets
are being identified every year.
For every new target discovered, there are 100 hopeful Flemings
looking for the next potential penicillin in the proverbial
petri dish.
The lion's share of such drug research has long involved
the interactions of small molecules with proteins or nucleic
acids. Carbohydrate recognition, which surely has important
biological activity given the volume of carbohydrates in the
body, has lagged behind the fields of protein and nucleic
acid recognition.
Even so, TSRI and Skaggs Institute for Chemical Biology
investigator Chi-Huey Wong, who holds the Ernest W. Hahn Professor
and Chair in Chemistry, suspects that times are changing.
As a chemist specializing in molecular manipulation, Wong's
major interest has long been in carbohydrate recognition.
He, for one, is interested in searching within that part of
the chemical universe hard to delve into up to now—the
part inhabited by carbohydrate structures—and he is not
alone. He predicts that in the near future, researchers will
pay much more attention to this area.
Carbohydrate Recognition
Carbohydrate structures are very much part of the language
of life. They are like the accents on spoken words—they
change the meaning without changing the spelling.
Some even call carbohydrates the third alphabet, behind
DNA and proteins. Though they are not charged with storing
genetic information like DNA or acting as enzymatic workhorses
like proteins, carbohydrates nevertheless do carry information
and are responsible for important biological functions, playing
a central role in many types of intercellular communication
events, particularly in the immune system.
All cells, foreign or human, are covered with them. Some
viruses, like HIV and influenza, use sugars on the outside
of human cells to gain entry, and immune system cells use
carbohydrate-binding proteins to detect subtle differences
in sugar structures on the surface of cells to recognize foreign
pathogens. Sometimes the carbohydrate-binding proteins and
their sugar ligands are expressed on the same cell, and the
sugar is part of the regulation machinery of the cell. Indeed,
the major histocompatability complex, which is responsible
for the recognition, is composed almost entirely of glycosylated
proteins.
Wong attributes the fact that carbohydrate recognition has
been much less studied than other areas of molecular recognition
but not due to any lack of interest on the part of biologists.
Part of the problem is the large number of polysaccharides
that exist.
The diversity of sugars is incredible. The human body contains
only nine monosaccharide building blocks from which it assembles
carbohydrate structures, but, unlike the components of nucleic
acid, they can link together in multiple, non-linear ways
because each building block has about four functional groups
for linkage. They can even form branched chains. Hence, the
number of possible polysaccharides is enormous—the number
of possible four-sacchraride chains you can form from the
nine monosaccharides is greater than 15 million.
An even greater barrier to studying polysaccharide recognition,
though, is that the structures are difficult to work with.
"We simply do not have the tools to study [carbohydrate
recognition]," says Wong. "We don't have PCR for amplifying
sugars and we don't have a machine for synthesizing sugars."
One-Pot Synthesis
The lack of commercially available or easy-to-make carbohydrate
structures has been called the single biggest bottleneck in
the field. And nobody is more aware of this problem than Wong,
who has worked arduously in recent years to design methodologies
for supplying carbohydrate structures.
The basic technique that Wong uses is one he designed a
few years ago, called programmable one-pot synthesis. This
technique basically involves placing a large number of specific
chemical building blocks into a reaction vessel and then making
sequential chemical reactions in the soup. The final products
depend entirely on the particular reaction scheme followed.
The one-pot technique allows Wong to quickly assemble many
types of carbohydrate structures—in just minutes or hours,
depending on how complicated the chemistry is. Wong even developed
software that he uses to streamline the process. "The computer
will tell you which building blocks to use and you simply
add them in sequence," he explains.
Depending on the type of building blocks used and the size
of the final structures, the pool of compounds made in this
way can be quite large. For instance, placing 300 building
blocks in a pot and randomly combining them into tetramers
will yield over eight billion compounds.
Once the oligosaccharides are made, these carbohydrate "libraries"
can be used for any number of biological studies. One of Wong's
main uses for the libraries is screening against various types
of biological targets to look for interactions.
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