University of Wisconsin at Madison researchers Jon Thorson, Changsheng Zhang, and Byron Griffith are using enzymes called glycosyltransferases to transform known, older medications into as many as 70 new ones.

The body normally uses the enzymes to move sugar molecules from one place to another on a variety of natural compounds, including some that doctors use to fight bacteria and fight cancer.

The University of Wisconsin team not only found a way to help the enzymes attach these sugars in different places on the same compound faster, but also discovered a way to cut them off from one compound and place them on another, giving scientists an almost unlimited capacity to make new drugs.

The team has already used the technique to make more than 70 variants of calicheamicin, a chemotherapy drug, and new versions of vancomycin, an antibiotic. Thorson told United Press International that sugar molecules are the "logistics specialists" of biochemistry.

"Sugars do many things for chemical compounds," he said. "They help them dissolve, guide them in and out of cells, bind them to specific target cells or special parts of a cell's structure, and help them get around a cell's resistance mechanisms."

Thorson added," Learning how to manipulate them easily allows us to make a large library of new compounds very quickly and identify the members of that library that can be beneficial in our fight against disease. A whole new area of biochemical diversity just opened up."

Thorson told UPI that chemical processes have been used in the past to move sugars around a molecule's structure, but the reactions had many steps and took a long time, making them impractical to use in drug development. He said the new method is a "one-pot reaction" that takes place quickly in a single test tube. The results are new drugs that retain the good properties of their parent compound, but discard the bad ones, or drugs that are precisely adapted to combat a particular disease.

"Digitoxin is a good case in point," Thorson remarked. "It regulates the sodium/potassium levels in the heart to help it recover from congestive heart failure and also has anticancer properties. We've made a version that is a stronger anticancer agent and has less effect on heart cells so it can be used in chemotherapy."

He added," This technology has the capacity to create chemotherapy drugs that zoom in on a hard-to-treat tumor, and create new antibiotics to which organisms are not yet resistant. There's a huge need for such drugs."

Although the team has only tested the new medications on cell cultures, they will try them out on animals in the near future and advance to human trials if these experiments are successful.

Alexandros Makriyannis, director of the Center for Drug Discovery at Northeastern University said he thought the team's work was valuable.

"This is a very nice advance in the field of carbohydrate chemistry that gives us the opportunity to perform difficult chemical procedures more quickly," Makriyannis told UPI. "It also gives sugars a bigger role in pharmacology. Old molecules can be altered to perform new functions and many new molecules will be discovered through this means."

Richard Gaynor, vice president for cancer research and global oncology platform leader for Eli Lilly and Co., was also encouraged by the discovery.

"Natural products are important in cancer therapeutics," Gaynor said. "Although preliminary, this work could have the ability to potentially improve the efficacy or reduce the toxicity of natural-product anticancer agents."

Thorson said that a Madison-based company called Centrose was currently preparing the technique for commercial use.

The research appears in the Sep. 1 issue of the journal Science.

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