2022 Nobel Prize in Chemistry Awarded for a New Way of Building Molecules

2022 Nobel Prize in Chemistry Awarded for a New Way of Building Molecules
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Three researchers won the Nobel Prize in Chemistry on Wednesday for their discovery of methods to “click” molecular building blocks together, forming complex molecules that can be used in applications ranging from drug development to crafting entirely new materials.

Morten Meldal of the University of Copenhagen and K. Barry Sharpless of Scripps Research in California won for their development, around the turn of the century, of “click chemistry”—a way to link two molecules together in a simple reaction that creates larger, more complicated forms of molecules with myriad capabilities. “It’s like building Legos,” a member of the Nobel committee said. This is the second Nobel for Sharpless, who won the prize in 2001 for designing specialized chemical reactions. (Read more about his initial prize in this Scientific American article.)

Carolyn Bertozzi of Stanford University took click chemistry into the realm of living cells. In a method called “bio-orthogonal chemistry,” Bertozzi figured out how to attach light-emitting compounds to biological molecules within a cell. This enabled her and other scientists to track these molecules around the cell, thus learning how the molecules contribute to disease—and how to develop drugs to combat the illness process.

“I’m absolutely stunned,” Bertozzi said, when reached by phone from the Nobel announcement news conference and told she had won the prize. “I’m still not entirely positive this is real. But it’s getting realer by the minute.” Bertozzi is the eighth woman to win the chemistry Nobel.

Life is filled with large, complicated molecules, and for decades chemists had repeatedly stumbled in their efforts to recreate them. Many attempts resulted in unwanted side reactions, making attempts to synthesize useful drugs and novel materials slow and expensive. Sharpless and Meldal’s insight was to start small. They took several simple molecules and added copper atoms, which helped the small molecular building blocks combine into a larger form. The two reseachers’ breakthrough achievement was published in 2002, independently, in separate papers. The scientists showed that two small molecules, an azide and a alkyne, could—with the help of copper—be locked together into a multi-part ring. The process is called the copper catalysed azide-alkyne reaction. Meldal showed that copper controlled the reaction. Sharpless demonstrated that the azide acts like a loaded spring whose force is released by the copper, and then it jumps forward into the alkyne.

Clicking in these molecules allows chemists to easily change the behavior of a material. Clickable components can improve a substance’s ability to conduct electricity or repel bacteria, or to help map a DNA sequence.

But copper does not work well in living cells. It is, in fact, toxic, and disrupts biological processes. Thus it could not be used to click molecules together within a cell. Bertozzi solved that problem by altering the configuration of the alkyne. She forced the molecule into a ring-shaped structure, which contained a great deal of energy. The added energy made the alkyne “explode” into a nearby azide, linking the two molecules together.

This basic approach made it possible to attach other molecules. Bertozzi was able to lock glowing fluorescent substances onto cell surface molecules called glycans, and then to use this light to track the movement of glycans on the cell. The process revealed aspects of cell development, and also ways in which cancer cells progress. Notably, Bertozzi’s bio-orthogonal chemistry has helped researchers develop new types of cancer drugs. Glycans seem to protect tumor cells—so researchers have joined antibodies that home in on glycans to enzymes that break glycans down. Without the glycans, tumor cells should be more vulnerable to attack by the body’s immune system. These antibody drugs are currently being tested for effectiveness in people.

“This work has had an enormous impact across science,” said Olof Ramström, a member of the Nobel chemistry committee, during the prize announcement. The three researchers will share the Nobel award equivalent to $915,000, and are set to attend the prize ceremony in December in Stockholm.

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    Josh Fischman is a senior editor at Scientific American who covers medicine, biology and science policy. He has written and edited about

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