Sometimes, things just click. And when they do, it can open up whole new worlds of opportunity. In chemistry, this kind of click resounded a couple of decades ago, when various scientists converged on new and efficient ways to “snap molecular entities” together quickly and efficiently – sometimes to even “live” in living systems.
The discoveries of click and bio-orthogonal chemistries have gone on to spark new potentials, including more environmentally friendly chemical processes and more targeted medicines, as well as discovering more about how cells respond to viruses and disease. And this month, Barry Sharpless, Morten Meldal and Carolyn Bertozzi will receive the Nobel Prize in Chemistry in 2022 for those insights.
Waiting for the click
One person who was not surprised by the Nobel nod for click and bio-orthogonal chemistries was Dr Elisa Fadda, a glycobiologist at Maynooth University.
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“I had been expecting this for years,” she says, describing how her lab was together for its regular group meeting at the time that the chemistry Nobel was being announced. “One of my students brought up the live feed on his phone, but I don’t speak Swedish so I didn’t understand a bit of it,” says Dr Fadda.
That was until she heard the names Morton Meldal and Barry Sharpless, who independently invented click chemistry, and Carolyn Bertozzi, who discovered bio-orthogonal chemistry that can run in living systems.
“We started screaming and jumping around, I was as excited as if my native Italy had won the World Cup,” Dr Fadda recalls. “We put a picture up on Twitter of our group celebrating and Carolyn Bertozzi liked it, she has been a huge supporter of our work, it was all just incredible.”
Efficiency upgrade
So what exactly is click chemistry? It’s a decades-old chemical reaction that got a serious efficiency upgrade around the 2000s, explains associate professor Andrew Kellett at Dublin City University, who today uses click chemistry to develop DNA-based medicines.
“The reaction on which click chemistry is founded was first understood back in the late 1950s and early 1960s, where an azide chemical group reacts with an alkyne chemical group and they lock together very specifically and tightly,” explains Prof Kellett.
This early reaction was inefficient though, and decades later, Barry Sharpless and Morton Meldal each found that using copper as a catalyst could make this reaction faster, more specific and more environmentally friendly.
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“The copper-catalysed reaction could be carried out in water, you didn’t need harsh solvents and you got high yields of a ‘clean’ product,” says Prof Kellett. “This was the cream of the crop in terms of catalysing the reaction, it was a game-changer.”
All very interesting, but why was this important? Because the “click” between the azide and the alkyne provides a backbone to connect other chemicals together, Prof Kellett says. “If you attach one chemical to the azide and a different chemical to the alkyne and then click the azide and alkyne together like jigsaw pieces or Lego, the attached chemicals are now connected too.”
Clicking into biology
This snappy chemical connection is useful for biomolecules, notes Prof Kellett, who is associate professor of inorganic and medicinal chemistry in DCU School of Chemical Sciences. “Biological systems don’t really interact with azides and alkynes,” he adds. “So when you are working with biological molecules the azides and alkynes react with each other to create that click, rather than with the biological molecules around them.”
Prof Kellett and his group in DCU now use click chemistry to make DNA-based molecules in the lab that could work as medicines of the future.
The challenge now is to bring the functionalised nucleic acids into cells, and we are making progress
— Andrew Kellett, Dublin City University
“We work on nucleic acids, which are naturally occurring types of molecules in cells, such as DNA. We use click chemistry to create molecules that can specifically attach to a piece of DNA. Then these molecules are also bound through click chemistry to an agent such as platinum drug that can stop the DNA working,” he says.
“This approach could be the basis of a really specific medicine, and we are looking to target cancer-related genes in breast cancer and glioblastoma.”
Ditching copper
There is a deal-breaker for click chemistry in living systems though: copper, the cream-of-the-crop catalyst for clicking, is toxic at high concentrations. Enter bio-orthogonal chemistry, the brainchild of Stanford professor Carolyn Bertozzi.
“Her approach was very clever,” Prof Kellett points out. “She created an alkyne in a ring-shaped structure that has a strain in it, so when the azide comes in contact with this alkyne, you don’t need copper as a catalyst, the strain means that the alkyne is spring-loaded and ready to react.”
Prof Kellett recently secured funding from the Irish Research Council and SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals, to bring his nucleic acid work into living systems.
“The challenge now is to bring the functionalised nucleic acids into cells, and we are making progress,” he says. “So far we have used both copper-catalysed and strain-promoted click chemistry in the lab, and they both work beautifully.”
Sugar coating cells
For Dr Fadda, her challenge of interest is to understand the coating of sugar molecules on the outsides of cells – a forest of important information that has come into sharper focus in recent years.
“Our cells are not bare, quite the opposite, they are covered in a sugar coat of glycans that changes quite dramatically in response to different states of cells, particularly between health and disease,” adds Dr Fadda, who is an associate professor in the Department of Chemistry and the Hamilton Institute at Maynooth University.
Carolyn Bertozzi’s discovery really provided us with the tools to start discovering this part of biology that had been ignored for so long
— Dr Elisa Fadda, Maynooth University
The “glyco-code” of this sugar coat is difficult to decipher, but Prof Bertozzi’s work has revolutionalised how we can examine it, explains Dr Fadda, because now we can label chemical structures in the coat while the cells are living, rather than needing to kill the cells in the process of examining them.
“Glycans or sugars speak a language we don’t understand, we can’t see them, but Carolyn Bertozzi realised that the enzymes that build those glycan structures can tolerate a slight modification of the sugars. So she was able to tag the sugars with a label, then make that label light up on the living cell, and we got these beautiful images of the glycans glowing in living systems. She was able to adapt click chemistry to a living cell environment, maintaining the cell living without disturbing it – it really was a magnificent thing.”
Prof Bertozzi’s work has opened up the way to understanding how the sugar coat changes in conditions such as cancer, and her insights reverberate across the field of glycobiology, says Dr Fadda, who recently helped to discover how SARS-CoV-2, the Covid-19 virus, can use a shield of sugars around its spike protein to hide from the host’s immune system as it invades.
“Carolyn Bertozzi’s discovery really provided us with the tools to start discovering this part of biology that had been ignored for so long,” she says. “Thanks to her insights, we are now able to better explore changes in the sugar coat, when and how it alters its appearance, and how this affects how the cell reacts with everything around it. Once you know that, you can come up with ways to decipher this glyco-code, and this is leading to new ways to intervene in medicine.”
