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.


Next Page | Carbohydrate Chips and Multiple Targets

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Chi-Huey Wong is Ernest W. Hahn Professor and Chair in Chemistry, and Member of The Skaggs Institute for Chemical Biology. Photo by Jeff Tippett.