Chemistry community reacts to Nobel Prize for "click chemistry"

Professor Jennifer A. Prescher from the Department of Chemistry at University of California, Irvine, worked with Carolyn Bertozzi during her time at UC Berkeley. Prof Prescher said: “I couldn't be more proud. It couldn’t happen to a more amazing scientist and person. I think that Carolyn is one of the most inspiring individuals I've ever met. And I think that that is the feeling that she invokes in most people…

“I even remember her chatting over the years with my parents who had come to visit me while I was in grad school – my parents had not been to college or anything and didn't have a deep understanding of chemistry. She could explain things to every person and make her science relatable and understandable to the masses – she taught my dad about NMR! And, you know, my parents still understand how these reactions work. And I think that is just one of many examples of just what an inspiring person she is – and a phenomenal educator.”

Tom Brown, Professor of Nucleic Acid Chemistry, Departments of Chemistry and Oncology, University of Oxford said: "The concept of click chemistry, initially pioneered by Barry Sharpless 20 years ago aided by his colleagues Valeri Fokin and M.G. Finn, has been transformative in many areas of chemistry, materials science, biology and medicine. It has given rise to new highly functional materials, has catalysed important pharmaceutical developments and has been influential in many areas of chemical biology.

“The archetypal click reaction is Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), the copper-catalysed version of the original Huisgen reaction. The CuAAC reaction makes exclusively 1,4-disubstitted 1,2,3-triazoles. It can be looked upon as a molecular ‘superglue’ or ‘molecular lego’ to join molecules together. It was discovered simultaneously by Sharpless and Meldal. It is an extremely efficient reaction, and crucially it is orthogonal to most other chemical reactions, and can be carried out in most media including water. These properties, particularly the fact that it is ‘invisible’ to other functional groups an molecules, make it incredibly flexible and broadly applicable. Applications are almost endless, for example it has been of enormous value to our own research in the nucleic acids field.

“The remarkable work of Carolyn Bertozzi has given rise to new types of click reactions that do not require copper catalysis, termed ‘Bioorthogonal click chemistry’. This concept can be used in applications where the CuAAC reaction and related metal ion catalysed reactions are not possible due to the toxicity of the metals. An example of Bioorthogonal click chemistry’ is the SPAAC reaction (Strain-promoted alkyne-azide cycloaddition) involving the reaction of an azide with a strained cyclooctyne. Importantly Bertozzi’s work enables click reactions to be done in living systems. It enables the visualisation of molecules in living cells and organisms, the study of disease processes, and development of new drugs including improvements in drug delivery. It has very been used to great effect in the study of glycans (polysaccharides) that play a major role in all essential functions of the human body, including the immune system.

“This is Sharpless’s second Nobel Prize in Chemistry, a stunning achievement. Anyone who knows him will testify that he is a unique character who is remarkably imaginative and passionate about chemistry.”

Dr Phillip Broadwith, from the Royal Society of Chemistry’s magazine Chemistry World, sums up the exciting chemistry behind this year’s Nobel prize. He said: “This is a prize that has been predicted for several years. It’s about having ultimate control over chemical reactions – Barry Sharpless coined the term Click Chemistry for reactions that are fast, high-yielding and clean – they don’t produce lots of side products.

“Carolyn Bertozzi’s work developing reaction that can be done inside living organisms, without harming them, has opened up a world of understanding of biochemistry – particularly the sugars that are attached to proteins that can define their functions – before her tools there was essentially no way to study those.

“One of the first ‘click reactions’ was independently discovered by both Sharpless and Morton Meldal, and has since sprouted its own branch of synthetic chemistry, being used to build molecules in new ways, and because some variants can work in live cells it can reveal biochemical processes too.

“Mostly these click reaction have been used to allow people to see processes happening in cells – like in cancer or other diseases. They allow researchers to get a true picture of the fundamental science and processes, which is something you couldn't do without this work. This is being explored to develop cancer treatments that 'click' together inside the body, so the potential is huge".

Professor David O’Hagan from the University of St Andrews Centre for Biomolecular Sciences, Department of Chemistry said: "This is a wonderful Prize which recognises the importance and impact that the ‘click’ reaction has had in a relatively short period of time since the separate but contemporaneous disclosures by Morten Meldal and Barry Sharpless, star-bursting across all areas of molecular science and opening up new opportunities in assembling complex molecules.

"It is now used every day in chemistry labs all over the world as it is clean and efficient in connecting small molecules to each other, or small molecules to larger biomolecules extending to intra-cellular reactions and nanoparticles, essentially right across the molecular scale range.

"The efficient snapping together of two molecules is impacting in the discovery of drugs, and with the modifications pioneered by Carolyn Bertozzi is being applied very widely to the development of tools for chemical biology, probing biochemical processes and in the development of molecular therapies such as tools for imaging and diagnosis.  The 2022 Award is also noteworthy in that Barry Sharpless receives a second Nobel Prize in Chemistry, a very rare event and it highlights an extraordinary career and one to be truly celebrated by the scientific community."

Professor Stuart Conway is the E. P. Abraham Cephalosporin Fellow at St Hugh's College, University of Oxford. He said: “Like many other Nobel Prizes in Chemistry, click chemistry gives us new ways of making molecules that would otherwise be hard to synthesise. In addition, click chemistry gives us new contexts in which we can carry out chemical reactions.

"Bertozzi and her research group have used chemistry, including click chemistry, that is inert to biological systems to carry out chemical reactions in living organisms. This has allowed her, and thousands of other researchers, to study the molecular details of biological systems in a way that was previously impossible.

"Click chemistry is now in everyday use by scientists from many disciplines, including those working on the chemistry-biology interface. One current example of click chemistry and biorthogonal chemistry is the study of drug assembly inside living systems, to ensure that these drugs reach their intended targets.”

Prof Robert Field, Professor of Chemistry at the University of Manchester, said: “Biorthogonal ligation chemistry provides powerful molecule- and site-specific approaches to dissect chemistry in vivo. The ability to gain spatial and temporal information about which molecules are where, when and attached to what is proving transformative.

"The impact of early discoveries is evidenced by the plethora of new reagents, reactions and biological applications that Bertozzi’s inspirational work in glycoscience have fostered. And only the tip of the iceberg has been sampled. A new age of chemical interrogation of complex biological systems awaits, with potential for application right across biology and medicine."

Prof Alison Hulme, from the School of Chemistry at the University of Edinburgh, said: "These three chemists have transformed the way that chemistry is applied to biology. For Barry Sharpless and Morten Meldal it started with “click” chemistry, in which two perfectly matched partners are coupled. The chemical components needed are now commercially available and “click” chemistry has revolutionised how biology labs around the world study biological interactions.

"This has been taken to a whole new level by Carolyn Bertozzi, who has developed click chemistry reactions that can take place inside living cells and organisms. The chemical components used must not react with the natural chemical components of the cell, but have their own separate so-called “bioorthogonal” chemistry. This more advanced approach is really allowing us to unpick complex biology at a molecular level.

"In our own labs we have used click chemistry to make a luminescent sensor for the presence of copper and we are using bioorthogonal reactions to track T-cells that are used in cancer therapies."

Royal Society of Chemistry Head of Global Inclusion, Dr Ale Palermo, said: "In addition to the deserved recognition for the promise and impact of scientific achievement, this year's Nobel prize awarded to Carolyn Bertozzi represents a unique opportunity to boost the visibility of LGBT+ scientists, whose work has been overlooked for so long and continues to be in so many places. This should be a great step to celebrate the diversity of our community and to welcome everyone to our discipline".

Jason Hein, Associate Professor at the University of British Columbia, Vancouver, was a postdoc with Barry Sharpless. He said: “Barry’s vision was to find reactions that would work anytime, anywhere and do only what you wanted them to do. He was striving to find way of instantly making any molecular connection you wanted. By laying out the philosophical guidelines in the original Angew Chem Article (Angewandte Chemie (International ed in English) 40, 2004–2021 (2001)) he created the foundation for a new class of ultra-reliable reactions termed click chemistry.

“This allowed an entire generation of researchers to find and tune reactions that met these criteria, leading to the CuAAc, SPAAC, and SuFEx modes of molecular unification. These tools opened the door from new, creative applications of synthetic chemistry in the harshest and most complicated environments including living cells. It all started because Barry demanded that we found reactions that just had to work.”

Professor Ali Tavassoli is President of the Royal Society of Chemistry’s Chemistry Biology Interface Community and Professor of Chemical Biology at the University of Southampton. He said: “Click chemistry and bio-orthogonal chemistry have significantly impacted scientific research with wide-reaching uses in multiple fields. These are amazing reactions, where the two reacting specie find each other at low concentrations, remaining specific in a soup of multiple functional groups. This award is a testament to the importance of research at the interface of chemistry and biology.”