Three scientists win chemistry Nobel Prize for developing ‘click’ and ‘bioorthogonal’ chemistry

Carolyn Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen, and K. Barry Sharpless of Scripps Research won the Nobel Prize in chemistry on Wednesday “for the development of click chemistry and bioorthogonal chemistry,” methods that have been applied in drug development and studying disease.

Click chemistry, true to its name, “clicks” together molecules much more easily and precisely than traditional chemical reactions. Sharpless coined the idea of click chemistry around 2000, and Meldal and Sharpless developed click reactions independently of each other shortly after. Bertozzi, interested in studying the sugar molecules called glycans on the surfaces of cells, a few years later developed click reactions that were possible without the copper catalyst, which allowed the reaction to occur in cells and the visualization of these glycans — which she termed “bioorthogonal chemistry.”

“Dr. Bertozzi has given us the tools to understand and manipulate sugars, not just in a test tube but in living cells,” Eric Rubin, editor in chief of the New England Journal of Medicine, told STAT. “The tools she has made open up new avenues for understanding how cells interact with each other and their environments and offer up new avenues for intervening in diseases such as cancer and infections.”

The prize was awarded by the Royal Swedish Academy of Sciences in Stockholm. Reached by phone right after the prize announcement, Bertozzi said she was stunned. “I’m still not entirely positive that it’s real,” she said, “but it’s getting realer by the minute.”

This award is the second Nobel for Sharpless, who won shared the chemistry prize in 2001 “for his work on chirally catalyzed oxidation reactions.” He’s now the fifth person to achieve the double honor, along with Marie Curie, Linus Pauling, John Bardeen, and Frederick Sanger.

Click chemistry has applications in drug development and delivery, DNA sequencing, and functional materials as well as studying biologic processes, which allows a better understanding of disease and therapeutics to treat them. As Bertozzi put it, one impact has been “doing chemistry inside of human patients to make sure drugs go to the right place and not to the wrong place.”

“A technique like this could be very important in terms of thinking about personalized medicine,” said Angela Wilson, president of the American Chemical Society, because this chemistry allows scientists to target specific cells and specific molecules within cells.

According to chemist M.G. Finn, who completed his Ph.D. with Sharpless and later collaborated with him on the click chemistry work, Sharpless intended the method to have a “much broader impact than most chemistry does in the world, or at least to enable many more people than just specialized chemists to access the advantages of making bonds.”

When synthesizing molecules — bringing two molecules together to create one larger molecule — there is always the chance for side reactions, where the molecules don’t react in the desired way and create unwanted side products instead. This is especially true in biological contexts, where there are many metabolites and other biomolecules floating around.

What if, as Finn put it, “molecular entities could be found that would have the power of making connections and ignoring everything else around them?” If one could find the right combination of molecule types that would readily react with each other only and not any other molecules that might be present (“orthogonal” chemistry), it would unlock many new applications.

Meldal and collaborator Christian W. Tornøe figured out a way to speed up this reaction: by using a copper catalyst. Meldal presented the results at a conference in 2001. Shortly after, Sharpless and Valery V. Fokin independently published a paper detailing a click reaction with a copper catalyst, but one that was simpler and cheaper.

The copper-catalyzed azide-click reaction has become widely used throughout the chemistry field. “You couldn’t browse through a [table of contents] of a chemistry journal without seeing someone using click chemistry to do something,” Stuart Cantrill, editorial director at Nature, told STAT. The reaction has especially found use in the polymers and materials chemistry fields.

Bertozzi, a chemical biologist and glycoscientist, wanted to learn about the little-studied sugar molecules called glycans coating our cells, and needed to be able to visualize these glycans to do so. Click chemistry, with its inherent modularity, seemed like the right approach for attaching a fluorescent tag to glycans that would be visible on a microscope. Additionally, the relatively unusual “buckle” functional groups for click chemistry weren’t naturally found in biological systems, so side reactions wouldn’t be a problem. However, the copper catalyst was not compatible with doing this chemistry in biological systems, as the copper had cytotoxic effects.

Instead of using a copper catalyst, Bertozzi took advantage of the strain in certain cyclic molecules called cycloalkynes that were forced into highly energetic configurations. The energy released by relieving the strain in the molecule helped drive the click reaction. The Bertozzi group figured out how to “sneak” one half of the click “buckle” molecules into the carbohydrates on the cell surface by feeding it into the metabolic cycle, said Jenn Prescher, who worked with Bertozzi as a graduate student and who now is a professor at the University of California, Irvine, which allowed them to do the strain-promoted click reactions on cells.

Prescher recalled the night she and co-author Nick Agard saw the first plots come out of the instrument, indicating that their approach to tagging cultured cells with fluorescent molecules was successful.

“Did we think that it would translate to being recognized with the Nobel Prize?” said Prescher. “Probably not at the time, but as the field has grown over the years I’ve certainly never forgotten that moment.”

During the call, Bertozzi recognized the graduate students and postdoctoral fellows she’s worked with over the past 25 years.

“It’s an opportunity for me to reflect on how fortunate I have been and to share in this celebration with them,” she said.

Bertozzi’s work has spun out many biotech startups, including Lycia Therapeutics, which focuses on degrading previously “undruggable” extracellular protein targets, and Redwood Bioscience, which was later acquired by Catalent.

Bertozzi’s vision for glycoscience and bioorthogonal chemistry has been recognized with many awards, including a MacArthur Foundation “genius” grant in 1999, a 2022 STATUS List honor, and a Wolf Prize this year. The Wolf Prize is regarded as a Nobel indicator: Sharpless won the same year as his first Nobel in 2001.

Other scientists have pointed out that Finn is probably the chemist who’s come closest to winning a Nobel twice (both in 2001 and 2022) but hasn’t been named. Finn, however, said he wasn’t unhappy. “I’m certainly not the story here,” he said in a press call. “It is a delight and a privilege and everything you can think of to be able to have worked with Professor Sharpless and to continue to work with him, or at least to talk with him as frequently as I can.”

Many people had predicted click and bioorthogonal chemistry would eventually be honored with a Nobel, but Cantrill was especially pleased to see Meldal included on the prize, as his name has sometimes been overlooked on prize predictions.

The laureates will share 10 million Swedish kronor, or about $908,000. Their names are added to a list of chemistry Nobel winners that includes 191 people, only eight of whom — including Bertozzi — have been women. Bertozzi is the second openly LGBT scientist to win a Nobel this year, along with medicine prize recipient Svante Pääbo.

Elizabeth Cooney contributed reporting.