Genetically Engineered Glycosyltransferases Create New Drugs

Drug developers have used genetically engineered bacteria to produce a series of enzymes that were selected for their ability to add sugar residues to potential drug molecules and thereby modify and sometimes improve their mode of action.

Investigators at the University of Wisconsin (Madison, USA) fabricated new glycosyltransferase enzymes by generating random mutations in genes that make a naturally occurring enzyme. The altered genes were inserted into a bacterium, which generated a series of randomly mutated new enzymes. These enzyme variants were then tested in a high throughput screening system in which the attachment of sugar moieties to fluorescent molecules was detected by the loss of fluorescent signaling.

Results published in the September 9, 2007, online edition of Nature Chemical Biology indicated that the range of potential therapeutic agents that could be generated with the new technology included important anti-inflammatory and anti-cancer compounds, and antibiotics.

Senior author Dr. Jon Thorson, professor of pharmaceutical sciences at the University of Wisconsin, said, "We are assaying hundreds of very interesting drug-like molecules now with newly evolved glycosyltransferases. The ability to rapidly evolve these enzymes has opened a lot of doors. What is more, the work could lead to the creation of a "super bug,” an engineered bacterium that can perform the entire process in a laboratory dish. "There is no doubt that this is going to work in vivo,” said Dr. Thorson. "We can create a bug where you feed it sugars, and the compounds you want to hang those sugars onto arrive as new medicines.”


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