The Nobel Prize in Chemistry for 2022 has been awarded to Carolyn R. Bertozzi (USA), K. Barry Sharpless (USA), and Morten Meldal (Denmark), for their work in the field of click chemistry and bioorthogonal chemistry. The prize was awarded to them for developing an ingenious tool for building molecule. Researches on ‘click chemistry’ and bioorthogonal reactions have taken chemistry into the era of functionalism and are bringing the greatest benefit to the mankind. This research holds considerable significance for medicinal biochemistry as well as pharmaceutical industry. They were awarded 10 million Swedish kronor, to be shared equally among the three.
About the Research
Click Chemistry It is a functional field in which molecules snap together quickly and efficiently, just like a click. Chemists often try to recreate complex chemical molecules found in nature. Complex chemical molecules have applications mainly in the field of medicine, with regard to targeting and blocking pathogens in cells. However, this process being complicated and time-consuming, Barry Sharpless and his colleagues started with smaller molecules that already had a complete carbon frame instead of trying to wrangle reluctant carbon atoms into reacting with each other. These simple reactions had a strong intrinsic drive for the molecules to bond together as they avoided many of the side reactions with a minimal loss of material. This robust method for building molecules is called ‘click chemistry’. Though click chemistry could not provide exact copies of natural molecules, it would be possible to find molecules that fulfilled the same functions. If a reaction is able to occur in the presence of oxygen and in water, it is known as a reaction of click chemistry.
Carbon atoms are vital to the existence of life. Replicating reactions that involve bonds between carbon atoms is expensive and often leads to side-reactions. This research focused on using smaller molecules that already have a complete carbon frame and which could further be linked by using oxygen or nitrogen atoms as bridges.
Barry Sharpless Research The very first scientist to work on click chemistry, Barry Sharpless explored the assembly of molecules. Sharpless has also previously shared the Nobel Prize in 2001 for his work on chirally catalysed oxidation reactions. In early 2000s, Dr Sharpless published his independent research about copper-catalysed reactions between azides and alkynes. The reaction worked in water, which satisfied his basic criterion for click chemistry. Hence, he described this reaction as an ‘ideal’ click chemistry reaction. Morten Meldal was also working on finding potential pharmaceutical substances known as triazoles. Both Dr Meldal and Dr Sharpless independently but around the same time presented their work on copper-catalysed azide-alkyne cycloaddition (CuAAC), a reaction that is now widely used in areas such as medicinal chemistry. Carolyn R. Bertozzi further contributed to the field by developing click reactions that work inside living organisms. These bioorthogonal reactions do not disrupt the normal chemistry of the cell.
Dr Morten Meldal’s Research Dr Meldal was working on finding potential pharmaceutical substances in early 2000s. His team tried to react an alkyne (an unsaturated hydrocarbon that has at least one triple bond between two carbon atoms) and an acyl halide (a compound that has an acyl group—RCO—bonded to a halogen). They also added copper ions and palladium as catalysts to speed up the chemical reaction. (Catalysts do not undergo any change in themselves while the chemical reaction takes place, but help in the chemical reaction.) It resulted in the alkyne reacting with the ‘wrong’ end of the acyl halide molecule—an azide group that contained nitrogen at the opposite end. The alkyne and the azide created a ring-shaped structure, called triazole.
These triazoles are useful compounds that have wide-range of applications in the pharmaceutical industry. It is also used in other areas like agriculture and material science. Meldal realised that copper ions were able to control the reaction and even the acyl halide mostly remained untouched.
Carolyn R. Bertozzi’s Research Dr Bertozzi’s research found that glycans, the complex carbohydrates built from different types of sugar, are often found on the surface of proteins and cells. To map important but elusive biomolecules on the surface of cells (glycans), she developed click reactions that work inside living organisms. Thus, Carolyn Bertozzi took click chemistry to a new level.
In the early 1990s, Bertozzi began mapping glycan that attracts immune cells to lymph nodes, and it took her four years to understand how the glycan functioned. She then picked up the idea to explore the possibility of producing sialic acid with a type of chemical handle. Sialic acid is one of the sugars that could make up glycans. She planned to map glycans using the chemical handle if she could get the cells to incorporate the modified sialic acid in different glycans. She did it by attaching a fluorescent molecule to the handle. This would emit light that helps in revealing where the glycans were in the cell. To accomplish this, Bertozzi needed a chemical handle that would not react with any other substance in the cell. She called the reaction between handle and the fluorescent molecule ‘bioorthogonal’.
In 2000, Bertozzi found the optimal chemical handle—an azide. She modified the Staudinger reaction (a mild conversion of azide to amine), used it to connect a fluorescent molecule to the azide, and introduced it to glycans in cells. During that time, CuAAC reaction was gathering momentum. As copper was toxic to living beings, Dr Bertozzi’s handle, the azide, was involved in the reaction. Dr Bertozzi published the copper-free click reaction, called the strain-promoted alkyne-azide cycloaddition (SPAAC), and demonstrated that it could be used to track glycans. Her research, including her focus on glycans on the surface of tumour cells, has proved to be crucial in the field of biochemistry.
Significance of the Research
Due to their high selectivity and specificity, click chemistry reactions find wide-range applications in areas like drug conjugation, materials science, etc. The bioorthogonal reactions are extremely significant in medicinal biochemistry since they do not interact with any other substances around them.
These reactions are now used globally to explore cells and track biological processes. Using bioorthogonal reactions, researchers have improved the targeting of cancer pharmaceuticals, which are now being tested in clinical trials. Click chemistry and bioorthogonal reactions have taken chemistry into the era of functionalism. This is bringing the greatest benefit to humankind.
According to Dr Neal Devaraj, Professor of Chemistry at the University of California, this research will encourage translational applications with incredible potential in this field. The research will really change the way in which one thinks about organic chemistry and will open up a large number of potential applications of both academic and industrial importance.
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