3 share Nobel for molecular links
Click chemistry allows researchers easier study of reactions
The 2022 Nobel Prize in chemistry has been awarded to three scientists whose work harnessed the power of molecular interaction and introduced new, unobtrusive ways of studying the natural world.
Carolyn R. Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen and K. Barry Sharpless of Scripps Research will share the prize, which honors the scientists’ independent research that resulted in the development of what is known as click chemistry and bio-orthogonal chemistry. The three researchers will also split a prize of around $900,000. Their works have “led to a revolution in how chemists think about linking molecules together,” said Johan Aqvist, the chair of the Nobel Committee for Chemistry.
In winning the award Wednesday, Sharpless became the fifth person to win two Nobels, having received the chemistry prize in 2001 for his work on chirally catalyzed oxidation reactions. The other two-time winners were Marie Curie, John Bardeen, Linus Pauling and Frederick Sanger. Bertozzi also became the eighth woman to be awarded the chemistry prize, the latest since Emmanuelle Charpentier and Jennifer A. Doudna in 2020.
For scientists looking to understand molecular reactions, combining molecules in a controlled way can be difficult, especially in a delicate environment like a living cell, because everything is so closely connected. Often the surrounding molecules are disturbed in the process, changing the very thing a researcher wants to study.
In 2001, Sharpless and some of his colleagues published a paper introducing what he called click chemistry, a new way of approaching this kind of molecular control when applied to the creation of new drug compounds. The method would be based around one rule, he wrote: “All searches must be restricted to molecules that are easy to make.” Instead of trying to synthesize, or chemically create, molecules by forcing a difficult organic bond, Sharpless said, focus instead on bonds that form fast and produce stable byproducts. If done in the right way, the tougher bonds will form automatically, clicking into place. Think of them “as gifts of nature,” Sharpless wrote.
“What’s unique about click chemistry is that the two reagents, in the presence of hundreds of thousands of different types of molecules, they will only seek out each other and only give one product,” said Jiong Yang, a program director at the National Institute of General Medical Sciences who oversees Sharpless’ work. “That’s the basis of all this technical development.”
This shift in approach was soon followed by the discovery of a reaction called copper-catalyzed azide-alkyne cyclo addition, which put the theory into practice. Azides and alkynes are two types of molecules, and Meldal and Sharpless independently found that when they were combined, using copper as a catalyst, the reaction was fast and efficient and the product was stable. Now known as the “crown jewel of click chemistry,” the discovery was “like opening the floodgates,” Olof Ramstrom, a member of the Nobel Committee for Chemistry, said in a briefing after the laureates were announced. “We were using it everywhere, to build everything.”
Molecules could now be combined quickly, efficiently and without much fuss, and the applications immediately extended “beyond chemists,” said Angela Wilson, the president of the American Chemical Society. Material science, pharmaceutical development, tissue regeneration, brightening agents — “this just opens up a world of possibilities in terms of materials and polymers,” Wilson said. “It’s like putting Lego pieces together — you do it much more easily and are able to build bigger molecules.”
Jon Lorsch, the director of the National Institute of General Medical Sciences, also used the Lego analogy. “It allows you to assemble molecules in a fairly defined way, such that you can direct what’s attached to what easily.” Lorsch added, “Almost anything you look at these days, you can find an example of where this chemistry has been applied.”
During the award announcement, Bertozzi, who joined remotely, acknowledged the potential of her and her fellow laureates’ work. “The field of click chemistry is still in its early phases,” she said, adding that there were “many new reactions to be discovered and invented,” as well as new ways to integrate the science in industries such as biotechnology.
One such application is in “drug delivery,” which involves “doing chemistry inside living patients to make sure drugs go to the right place and not to the wrong place.”
But all those plans for the future came after her surprise, which registered when she first called in to the committee. “I’m absolutely stunned. I’m sitting here and can hardly breathe,” she said. “I’m still not entirely positive that it’s real — but it’s getting realer by the minute.”