The Nobel Prize in Chemistry 2022 has been awarded to
- Carolyn R. Bertozzi, Stanford University, CA, USA,
- Morten Meldal, University of Copenhagen, Denmark, and
- K. Barry Sharpless, Scripps Research, La Jolla, CA, USA,
for “the development of click chemistry and bioorthogonal chemistry” .
Barry Sharpless and Morten Meldal have laid the foundation for click chemistry—reactions in which molecular building blocks snap together quickly and efficiently. Carolyn Bertozzi has taken click chemistry to a new level and started using it in living organisms.
Barry Sharpless and Morten Meldal
Barry Sharpless, who is awarded his second Nobel Prize in Chemistry, developed the concept of click chemistry , which is a form of simple and reliable chemistry where reactions occur quickly and unwanted by-products are avoided. He argues that researchers could link simple molecules together using bridges of nitrogen or oxygen atoms. Combining simple chemical building blocks makes it possible to create an almost endless variety of molecules, which is particularly useful in drug development.
Shortly afterward, Morten Meldal and Barry Sharpless—independently of each other—presented what is now the perfect example of click chemistry: the copper-catalyzed azide-alkyne cycloaddition, giving triazoles. This is an elegant and efficient chemical reaction that is in widespread use. Among many other uses, it is used in the development of pharmaceuticals, for mapping DNA, and for creating functional materials.
Meldal discovered this reaction while trying to react an alkyne with an acyl halide in the presence of copper ions. He found that the alkyne had reacted with an azide group that was present in the acyl halide reaction partner, forming a triazole. He first presented his discovery at a symposium in 2001 and published an article in 2002 .
The same year, Sharpless published a paper about the copper-catalyzed azide-alkyne cycloaddition , showing that the reaction works in water and is reliable. He described it as an “ideal” click reaction. Sharpless proposed that chemists can use the reaction to easily link different molecules, which turned out to be right. If chemists want to link two different molecules they can now, relatively easily, introduce an azide in one molecule and an alkyne in the other. They then “snap” the molecules together with the help of some copper ions.
Carolyn Bertozzi took click chemistry to a new level. To map glycanes on the surface of cells, she developed click reactions that work inside living organisms. Mapping glycans had been challenging due to a lack of efficient tools. Bertozzi wondered whether she could get cells to produce a sialic acid—one of the sugars that build up glycans—with a chemical handle, making the glycans easier to map. She could, for example, then attach a fluorescent molecule to the handle.
In 2000, Bertozzi found the optimal chemical handle: an azide . She modified a Staudinger reaction and used it to connect a fluorescent molecule to the azide she had introduced to the cells’ glycans. Because the azide does not affect the cells, it can be introduced into living organisms.
With azides as a chemical handle on cells, the copper-catalyzed azide-alkyne cycloaddition was also interesting for the functionalization of biomolecules—but copper is toxic. Thus, Bertozzi developed a copper-free click reaction, called the strain-promoted alkyne-azide cycloaddition . This is based on the observation that azides and alkynes can react without the help of copper if the alkyne is forced into a ring-shaped chemical structure.
Bertozzi’s bioorthogonal reactions take place without disrupting the normal chemistry of the cell. These reactions are widely used to explore cells and track biological processes. Using bioorthogonal reactions, researchers have, e.g., improved the targeting of anticancer drugs that are now being tested in clinical trials.
Carolyn Bertozzi, born in 1966 in the USA, studied chemistry at Harvard University, Cambridge, MA, USA, and at the University of California (UC) Berkeley, USA, where she received her Ph.D. in 1993. After postdoctoral work at UC San Francisco, USA, in the field of cellular immunology, she joined the faculty of UC Berkeley in 1996. In 2015, Carolyn Bertozzi joined Stanford University. Today, she serves as Anne T. and Robert M. Bass Professor of Chemistry and Professor of Chemical & Systems Biology and Radiology there, as well as an Investigator at the Howard Hughes Medical Institute.
Among many other honors, Carolyn Bertozzi has received the Ernst Schering Prize from the Schering Foundation in 2007, the Lemelson-MIT Prize from the Lemelson Foundation and the Massachusetts Institute of Technology (MIT) in 2010, the Heinrich Wieland Prize from the Boehringer Ingelheim Foundation in 2012, and the Arthur C. Cope Award from the American Chemical Society (ACS) in 2017. She is a Fellow of the U.S. National Academy of Inventors and of the American Association for the Advancement of Science (AAAS), as well as a Member of the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, and the German Academy of Sciences Leopoldina.
Morten P. Meldal, born on January 16, 1954, in Denmark, studied chemical engineering at the Technical University of Denmark (DTU), Lyngby, where he received his Ph.D. in 1983 on the synthesis of oligosaccharides. As a post-doctoral fellow, he was at the University of Cambridge, UK, at the MRC Laboratory of Molecular Biology. In 1996, he became a professor at the Technical University of Denmark. He also headed the Solid Phase Organic Combinatorial Chemistry Center at the Carlsberg Laboratory, Copenhagen, Denmark, with the rank of professor from 1988. In 2004, he received an honorary professorship in the Department of Pharmacy at the University of Copenhagen. In 2011, he became Professor of Nanochemistry at the University of Copenhagen’s Nano Science Center.
Among several other awards, Morten Meldal received the Ralph F. Hirschmann Award in Peptide Chemistry in 2009 and the Vincent du Vigneaud Award in 2011. He is a member of the Royal Danish Academy of Sciences.
K. Barry Sharpless, born on April 28, 1941, in Philadelphia, PA, USA, studied chemistry at Dartmouth College, Hanover, NH, USA, and Stanford University, CA, USA, where he received his Ph.D. in organic chemistry in 1968. He then performed postdoctoral research with James P. Collman at Stanford and with Konrad E. Bloch at Harvard University, Cambridge, MA, USA. In 1970, Barry Sharpless joined the Massachusetts Institute of Technology (MIT), Cambridge. From 1977 to 1980, he was part of the faculty at Stanford University. Since 1990, he is W. M. Keck Professor at the Scripps Research Institute.
Among many other honors, Barry Sharpless has received the Nobel Prize in Chemistry in 2001, together with William Standish Knowles and Ryōji Noyori, “for his work on chirally catalyzed oxidation reactions”, the 2019 Priestley Medal of the American Chemical Society (ACS), and the 2015 August Wilhelm von Hofmann Lecture of the German Chemical Society (GDCh).
 Hartmuth C. Kolb, M. G. Finn, K. Barry Sharpless, Click Chemistry: Diverse Chemical Function from a Few Good Reactions, Angew. Chem. Int. Ed. 2001, 40, 2004–2021. https://doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5
 Christian W. Tornøe, Caspar Christensen, Morten Meldal, Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides, J. Org. Chem. 2002, 67, 3057–3064. https://doi.org/10.1021/jo011148j
 Vsevolod V. Rostovtsev, Luke G. Green, Valery V. Fokin, K. Barry Sharpless, A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes, Angew. Chem. Int. Ed. 2002, 41, 2596–2599. https://doi.org/10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
 Eliana Saxon, Carolyn R. Bertozzi, Cell Surface Engineering by a Modified Staudinger Reaction, Science 2000, 287, 2007–2010. https://doi.org/10.1126/science.287.5460.2007
 Nicholas J. Agard, Jennifer A. Prescher, Carolyn R. Bertozzi, A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems, J. Am. Chem. Soc. 2004, 126, 15046–15047. https://doi.org/10.1021/ja044996f
Selected Publications by Carolyn R. Bertozzi
- Engineering Orthogonal Polypeptide GalNAc-Transferase and UDP-Sugar Pairs,
Junwon Choi, Lauren J. S. Wagner, Suzanne B. P. E. Timmermans, Stacy A. Malaker, Benjamin Schumann, Melissa A. Gray, Marjoke F. Debets, Megumi Takashima, Jase Gehring, Carolyn R. Bertozzi,
J. Am. Chem. Soc. 2019, 141, 13442–13453.
- Acute Modulation of Mycobacterial Cell Envelope Biogenesis by Front-Line Tuberculosis Drugs,
Frances P. Rodriguez-Rivera, Xiaoxue Zhou, Julie A. Theriot, Carolyn R. Bertozzi,
Angew. Chem. Int. Ed. 2018, 57, 5267–5272.
- Multiple Click-Selective tRNA Synthetases Expand Mammalian Cell-Specific Proteomics,
Andrew C. Yang, Haley du Bois, Niclas Olsson, David Gate, Benoit Lehallier, Daniela Berdnik, Kyle D. Brewer, Carolyn R. Bertozzi, Joshua E. Elias, Tony Wyss-Coray,
J. Am. Chem. Soc. 2018, 140, 7046–7051.
- Cu-free click cycloaddition reactions in chemical biology,
John C. Jewett, Carolyn R. Bertozzi,
Chem. Soc. Rev. 2010, 39, 1272–1279.
- Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality,
Ellen M. Sletten, Carolyn R. Bertozzi,
Angew. Chem. Int. Ed. 2009, 48, 6974–6998.
- Copper-free click chemistry for dynamic in vivo imaging,
J. M. Baskin, J. A. Prescher, S. T. Laughlin, N. J. Agard, P. V. Chang, I. A. Miller, A. Lo, J. A. Codelli, C. R. Bertozzi,
Pro. Natl. Acad. Sci. USA 2007, 104, 16793–16797.
- Synthesis of Heterobifunctional Protein Fusions Using Copper-Free Click Chemistry and the Aldehyde Tag,
Jason E. Hudak, Robyn M. Barfield, Gregory W. de Hart, Patricia Grob, Eva Nogales, Carolyn R. Bertozzi, David Rabuka,
Angew. Chem. Int. Ed. 2012, 51(17), 4161–4165.
- Imaging the Sialome during Zebrafish Development with Copper-Free Click Chemistry,
Karen W. Dehnert, Jeremy M. Baskin, Scott T. Laughlin, Brendan J. Beahm, Natasha N. Naidu, Sharon L. Amacher, Carolyn R. Bertozzi,
ChemBioChem 2012, 13(3), 353–357.
Selected Publications by Morten P. Meldal
- Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12,
Daniel Madsen, Frederik P. Jorgensen, Daniel Palmer, Milena E. Roux, Jakob V. Olsen, Mikael Bols, Sanne Schoffelen, Frederik Diness, Morten Meldal,
ACS Combinatorial Science 2020, 22, 156–164.
- Recent advances in covalent, site-specific protein immobilization,
Morten Meldal, Sanne Schoffelen,
F1000Research 2016, 5, 2303.
- C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles,
J. Hansen, F. Diness, M. Meldal,
Organic & Biomolecular Chemistry 2016, 14, 3238–3245.
- In-vivo imaging of MMP-13 activity in the murine destabilised medial meniscus surgical model of osteoarthritis,
N. H. Lim, E. Meinjohanns, M. Meldal, G. Bou-Gharios, H. Nagase,
Osteoarthritis and Cartilage 2014, 22, 862–868.
- Maintaining Biological Activity by Using Triazoles as Disufide Bond Mimetics,
Kai Holland-Nell, Morten Meldal
Angew. Chem. Int. Ed. 2011.
- Cu-Catalyzed Azide−Alkyne Cycloaddition,
Morten Meldal, Christian Wenzel Tornø,
Chem. Rev. 2008, 108(8), 2952–3015.
- Polymer “Clicking” by CuAAC Reactions,
Macromolecula Rapid Communications 2008.
Selected Publications by K. Barry Sharpless
- SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization,
Zilei Liu, Jie Li, Suhua Li, Gencheng Li, K. Barry Sharpless, Peng Wu,
J. Am. Chem. Soc. 2018, 140, 2919–2925.
- A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt Emerging as an “F−SO2+” Donor of Unprecedented Reactivity, Selectivity, and Scope,
Taijie Guo, Genyi Meng, Xiongjie Zhan, Qian Yang, Tiancheng Ma, Long Xu, K. Barry Sharpless, Jiajia Dong,
Angew. Chem. Int. Ed. 2018, 57, 2605–2610.
- Quantitative and Orthogonal Formation and Reactivity of SuFEx Platforms,
Digvijay Gahtory, Rickdeb Sen, Sidharam Pujari, Suhua Li, Qinheng Zheng, John E. Moses, K. Barry Sharpless, Han Zuilhof,
Chem. Eur. J. 2018, 24, 10550–10556.
- Copper(I)-Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes,
Jason E. Hein, Jonathan C. Tripp, Larissa B. Krasnova, K. Barry Sharpless, Valery V. Fokin,
Angew. Chem. Int. Ed. 2009, 48, 8018–8021.
- Mechanistic Studies on the Cu-Catalyzed Three-Component Reactions of Sulfonyl Azides, 1-Alkynes and Amines, Alcohols, or Water: Dichotomy via a Common Pathway,
Eun Jeong Yoo, Mårten Ahlquist, Imhyuck Bae, K. Barry Sharpless, Valery V. Fokin, Sukbok Chang,
J. Org. Chem. 2008, 73, 5520–5528.
- Copper-Catalyzed Synthesis of N-Sulfonyl-1,2,3-triazoles: Controlling Selectivity,
Eun Jeong Yoo, Mårten Ahlquist, Seok Hwan Kim, Imhyuck Bae, Valery V. Fokin, K. Barry Sharpless, Sukbok Chang,
Angew. Chem. Int. Ed. 2007, 46, 1730–1733.
Also of Interest
- Nobel Prize in Physics 2022,
Alain Aspect, John F. Clauser, and Anton Zeilinger were honored for experiments with entangled photons, establishing the violation of Bell inequalities and pioneering quantum information science
- Nobel Prize in Physiology or Medicine 2022,
The prize was awarded to Svante Pääbo for his discoveries concerning the genomes of extinct hominins and human evolution
- Nobel Prize in Chemistry 2021,
The prize was awarded to Benjamin List (Germany) and David MacMillan (USA) for the development of asymmetric organocatalysis
- Chemistry Nobel Prize Quiz,
How much do you know about the Nobel Prize Laureates?
- Collection: Nobel Prize in Chemistry
Collection of interviews with Nobel Laureates and Nobel Prize quizzes