Carolyn Bertozzi, Morten Meldal and Barry Sharpless worked on click chemistry, or linking chemicals together, and biorthogonal reactions, that apply such chemistry to living cells
Carolyn Bertozzi, Morten Meldal and Barry Sharpless were awarded the 2022 Nobel Prize in Chemistry October 5 for their work on click chemistry and bioorthogonal reactions.
Click chemistry deals with linking chemicals together, while bioorthogonal reactions take click chemistry to living cells. The three scientists’ work is being explored for possible applications in cancer treatment, diagnostics and delivery of drugs.
“This year’s Prize in Chemistry deals with not overcomplicating matters, instead working with what is easy and simple. Functional molecules can be built even by taking a straightforward route,” Johan Åqvist, chair of the Nobel Committee for Chemistry was quoted as saying in a press statement.
In 2000, Sharpless from Scripps Research, United States, introduced the world to click chemistry.
This concept essentially clicks or links two building blocks together in a very efficient way, Olof Ramstrom, professor at the Center for Pathogen Research & Training (CPRT) and member, Nobel Committee for Chemistry 2022, said during the announcement.
“You will get a good amount of product in a reasonably short time,” the expert added.
Sharpless is a two-time Nobel laureate. He was awarded for the first time in 2001 for his work on chirally catalysed oxidation reactions.
Artificially linking carbon atoms has challenged chemists by creating numerous unwanted side reactions and material loss.
Click chemistry was proposed to make reactions fuss-free. But for a chemical reaction to qualify as click chemistry, it must occur in the presence of oxygen and water, which is cheap and environmentally friendly.
In the years that followed, Meldal from the University of Copenhagen, Denmark, demonstrated a chemical reaction that found applications in pharmaceuticals and creating other materials. Sharpless also independently presented this reaction shortly.
The “crown jewel of click chemistry” is the copper catalysed azide-alkyne cycloaddition. It is a reaction between azide (a structure with three nitrogen atoms in a row) and an alkyne (molecules that contain a triple bond between two carbon atoms).
“These two building blocks are not terribly reactive by themselves. If you mix them, they will react very sluggishly with one another,” Ramstrom said, adding that they often produce a mixture of products.
Meldal’s and Shapeless’ labs showed that adding copper dramatically speeds up the reaction. It gave rise to a useful product called triazole. It has numerous applications, from pharmaceuticals and dyes to agricultural chemicals, according to the Nobel Committee.
Since then, chemists have been able to link two different molecules relatively easily by introducing an azide in one molecule and an alkyne in the other and adding some copper ions.
“Although other reactions have been identified and discovered, this particular reaction [copper catalysed azide-alkyne cycloaddition] has almost become synonymous with the click reaction concept and is often called the click reaction,” Ramstrom said.
The other application was living cells. But there was a problem: copper is toxic to living beings. This means experts had to look for alternate means.
Around the time of click chemistry, Bertozzi from Stanford University, United States, proposed bioorthogonal reactions. These reactions allow click chemistry within living cells without needing a metal. They also don’t interfere with other chemical reactions happening within the cell.
The team demonstrated bioorthogonal reactions by twisting the shape of alkyne, allowing it to become more reactive. This was tested in cells cultured in the lab and also mice.
These bioorthogonal reactions helped Bertozzi and her colleagues map complex sugar structures lining cells called glycans.
“Her studies have led to the insight that some glycans appear to protect tumours from the body’s immune system, as they make the immune cells shut down,” read a note from the Nobel Committee of the Royal Swedish Academy.
Bertozzi and her colleagues developed a new type of biological pharmaceutical to block glycan’s protective function.
They combined an antibody that targets glycans with enzymes that break down the glycans. This potential anti-cancer drug is now being tested in clinical trials on people with advanced cancer, according to the Committee.
Additionally, bioorthogonal reactions can help researchers understand how biomolecules interact in cells and study diseases.
“These very important accomplishments from our Nobel laureates have made an enormous impact on chemistry and science in general,” Ramstrom highlighted.
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