Biologists have long sought chemical reactions that can home in on and alter particular molecules while leaving everything around them untouched. Their desire may soon be fulfilled. A team of chemists has developed a reaction that targets specific sugars that decorate proteins and other molecules. So far, the researchers have used the technique to study the embryonic development of zebrafish. But it could one day offer doctors better ways to deliver radioactive imaging agents to tumors or diseased blood vessels and catch cancer and heart disease in their earliest stages.
The advance is the latest in so-called click chemistry. In recent years, chemists have developed reactions that are highly selective, fast, work in water, and create no unwanted byproducts. The goal is to use those superslick reactions as tools to greatly simplify other, more difficult tasks. Six years ago, research groups in California and Denmark independently hit on perhaps the most powerful of these reactions, which uses a copper catalyst to join common chemical groups called azides and alkynes. The reaction has proven to be a hit among polymer chemists and materials scientists because it allows them to essentially click together molecules with different functions that previously couldn't easily be joined, allowing them, for example, to click biocompatible compounds onto polymers to make novel biomaterials. But the work didn't help biologists trying to carry out their reactions inside organisms because the copper catalyst was toxic.
Last year, researchers led by Carolyn Bertozzi, a chemist at the University of California, Berkeley, found a way around that problem. They bent the ordinarily sticklike alkyne into a ring, which prompted it to react quickly with azides without the need for the copper catalyst. They then fed sugars modified to carry azides to mice, whose bodies used them to decorate proteins and other biomolecules. The researchers then imaged the sugars in tissue samples from sacrificed rodents by adding fluorescently labeled alkynes that reacted with the azides. One advantage of this labeling scheme, Bertozzi says, is that it doesn't rely on introducing large fluorescent tags, such as the protein GFP, or large antibodies to target a traditional fluorophore, which can sometimes interfere with the tagging.
In this week's issue of Science , Bertozzi and her colleagues take a major step forward by extending the technique to track where specific sugars are deployed in living zebrafish embryos as they develop. To do that, the researchers added azides to the various sugars, fed them to the embryos, and later added the fluorescently labeled alkynes. Using the technique, the researchers were able to simultaneously track the distribution of numerous different sugar groups throughout development of the embryos. These sugars are thought to play important roles in everything from protein folding to regulation of communication between cells, but until now researchers have lacked a good way of visualizing them to help sort out their functions.
The new result is "a real tour de force at the interface of chemistry and biology," says Craig Hawker, a chemist at the University of California, Santa Barbara, and a specialist in click chemistry. The new reaction's potential extends far beyond imaging sugars on proteins and may one day improve medicine. Bertozzi's group, for example, is already adapting the technique to create tumor-imaging agents, and Hawker's group is using a related approach to observe heart disease in its formative stages.