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2022 Nobel Prize in Chemistry awarded to American chemist Carolyn Bertosi (Carolyn R. Bertozzi), Danish chemist Motten Meldal (Morten Meldal) and American chemist Karl Barry Sharpless, recognizes their contribution to the "development of click chemistry and bioorthogonal chemistry". Among them, Shapleis won the Nobel Prize for for for for the second time.
There are only 4 scientists who have won two Nobel Prizes in history, including Madame Curie (Physics Award, Chemistry Award), Bading (Physics Award, Physics Award), Pauling (Chemistry Award, Peace Award), and Sango (Chemistry Award, Chemistry Award). Today, American scientist Sharpless became the fifth scientist to win two Nobel Prizes. He won the award last time in 2001, and today he won the award for the second time. His last name Sharpless can be joked and misinterpreted as "not smart." Please allow us to have a little humor.
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According to the official website of the Nobel Prize, the work of Barry Sharpless and Morten Meldal laid the foundation for the functional form of chemistry - click chemistry - so that molecular structural units can be combined quickly and effectively. And Carolyn Bertozzi takes click chemistry to a new dimension and starts using it in organisms.
Carolyn Bertozzi's student and dean of the School of Chemistry of Peking University, Chen Xing, told Intellectuals: Bioorthogonal and click chemistry start from the specific and efficient way of biomarkers and organic synthesis of , respectively, and have achieved the same goal, becoming the most widely used chemical reaction in the fields of chemistry, life and materials science. Winning the Nobel Prize in Chemistry in 2022 reflects the power of organic chemistry and the charm of interdisciplinary disciplines.
Chen Xing sent a text message to Carolyn (note: the female scientist who won the award today) yesterday, and was still joking about whether she would win the award this year. Just after sending a congratulations text message, she replied with an "accidental horror" expression.
's rapid rise of hot spots:
New click chemistry technology highlights huge application prospects
Written by | Li Yan
Editor | Chen Xiaoxue
2014, the research team of Nobel Prize winner Karl Barry Sharpless reported a click chemistry reaction based on hexavalent sulfur-fluorofluoro exchange (SuFEx) on "German Applied Chemistry" (Angew. Chem. Int. Ed. ) . This is a very unique paper. The article reports original research results on the sulfonyl fluoride series reaction, but it is published in the form of a review (review) , and is a review with hundreds of pages of supplementary materials. This unprecedented unique way of reporting can be published highlights the authors and journal editors' high attention to this research result.
► Figure 1 . Image source: Angew. Chem. Int. Ed. 2014, 53, 9430
Hexavalent sulfur-fluorine exchange reaction is interesting and useful, but to fully understand the significance of the reaction, we also need to understand the grand concept of "click chemistry".
The concept of click chemistry is proposed
Click chemistry (Click Chemistry) , sometimes translated as link chemistry, is a synthesis concept first proposed by Professor Sharpless [2].
Review of the previous development of organic synthesis proposed by click chemistry concept. After , the United States dominated the forefront of this field after in World War II. Research work focuses on the synthesis of complex molecular structures (especially natural products) through the construction of carbon-carbon bond (C-C) , and all synthesis masters represented by R. B. Woodward and E. J. Corey emerged.Their work reflects people's courage to challenge nature, and some of the novel synthetic methods reported also make the content of organic chemistry richer and systematic, but these reactions are often not easily widely used by researchers in other fields because of their high operation difficulty or low yield.
nucleic acid and protein are common biological macromolecules in nature. The complex chemical structure and rich biological functions are achieved by the link of small molecule units with the help of carbon-heteroatomic bond (phosphate ester bond and peptide bond) . Inspired by this, Sharpless proposed the concept of click chemistry in 2001, emphasizing the synthesis of carbon heteroatom bonds (C-X-C) or even inorganic connections as the basis, and quickly and reliably complete the chemical synthesis of various molecules.
click chemistry advocates believe that in the intersection of chemistry and other disciplines (materials, biology) , chemical synthesis can be at a core position, its essence is to be a tool, and the complexity of the tool is often inversely proportional to its application. Pursuing overly professional and highly complex tools is to lose the foundation. The form of molecule (Form) is directly related to the function of molecule (Function), but more importantly, the function [3] is implemented.
As the saying goes, "A good sword is broken, and it is not expected to be a turtle; a good horse is a thousand miles long, but it is not expected to be a rude horse." The core idea of click chemistry seems to have some similarities with the simple and practical philosophical thoughts of ancient China.
The first classic of click chemical reaction
Following the introduction of the concept of click chemical, monovalent copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC reaction) was independently reported by the Sharpless and Medal groups in 2002. This reaction is the first classic in click chemistry.
azide and terminal alkyne remain stable under most chemical conditions, but can efficiently and specifically convert to 1,3-substituted triazole under monovalent copper catalytic conditions (Figure 2) . Link groups that are completely consistent with their structure have not been found in nature, but the characteristics of mild conditions, high yield, high chemical selectivity and no interference from water and oxygen have become outstanding advantages of this reaction. Although the significance of click chemistry is not only to reduce operational difficulty, relatively simple operation does create conditions for the widespread use of this technology. If photography technology is used to compare organic synthesis, then some difficult methods used in the synthesis of natural products are like SLR cameras that require repeated exploration to master, so that ordinary people can only appreciate it, but clicking on chemistry seems to be convenient for taking pictures on mobile phones, so that more people can easily get started.
► Figure 2
Hexavalent sulfur-fluorofluoro exchange reaction
CuAAC reaction has achieved great success, but this reaction also has weaknesses in application: azide groups must be introduced into organic compounds, which may pose a safety hazard when the reaction amplifies; the triazole produced by the cycloaddition reaction is a perfect link, but such compounds have a large polarity and a low solubility , which to a certain extent limit the application of this reaction in the materials field of synthetic polymers and the field of drug synthesis.
Based on the successful experience of CuAAC and the further development of click chemistry concepts, the Sharpless research team has reported on the synthesis of the hexavalent sulfur element fluoride and its unique reactivity since 2014. Similar to CuAAC reaction, we need to find a functional group that exists stably under basic chemical conditions but is super active in special cases.
Among high-valent sulfur compounds, arylsulfonyl chloride (such as Ts-Cl) is a commonly used electrophile reagent for organic chemists. Sulfonyl chloride (-SO2Cl) has high activity and is sensitive to moisture, so it has certain limitations in its application range. Fortunately, high-valent sulfhydryl fluorides can remain stable under most chemical conditions while being reactive, which is the functional group required by click chemistry.The initial reaction activity study of high-valent sulfhydryl fluoride can be traced back many years ago, but it did not attract relevant attention at that time. Professor Sharpless's team realized the importance of this type of compound and further developed it on the basis of the previous basis, opening up the exploration process of SuFEx reaction (Figure 3).
► Figure 3. Image source: Angew. Chem. Int. Ed. 2014, 53, 9466 (where Ref. 9 in the figure is V. Gembus, F. Marsais, V. Levacher, Synlett 2008: 1463, is one of the earliest literatures to study the reactivity of sulfonyl fluoride groups.) In the initial report of the reaction of
SuFEx, a commercially produced gas was used: sulfonyl fluoride (SO2F2). This is an fumigant , which is commonly used in the United States to eliminate termites and other pests in houses, but does not affect the walls and furnishings in the house at all. SO2F2 is very stable under normal conditions, but in specific cases, such as the presence of some organic base , the S-F bond can be activated, react with hydroxyl or siliconether to convert into S-O bonds, forming aryloxysulfonyl fluoride (Ar-O-SO2F) . It is particularly worth mentioning that the reactivity of SO2F2 with phenolic hydroxyl groups is significantly better than that of alcohol hydroxyl groups and amino groups. Ar-O-SO2F can further react with hydroxyl groups or silicone ethers, and the Ar-O-SO2-link formed has good stability and is much less sensitive to water gas than phosphate and other analogs (Figure 4) .
► Figure 4. Image source: Angew. Chem. Int. Ed. 2014, 53, 9430
SO2F2 gas can combine with imidazole group to form a salt and serve as a stable sulfonyl fluoride group donor. This solves the problem of inconvenient operation of SO2F2 gas, and the reaction activity of the sulfonyl fluorine group after binding will also be greatly improved, and it can directly react with primary amine (-NH2) [6] (Figure 5) . The research work was accepted by Angew. Chem. Int. Ed. in late 2017. In this paper, Professor Sharpless used the Shanghai Institute of Organics as his only communication unit [7] for the first time.
► Figure 5. Image source: Angew. Chem. Int. Ed. DOI: 10.1002/anie.201711964, ASAP
In addition to SO2F2 gas, another hexavalent sulfur gas SOF4 has recently entered the research field of the Sharpless research group [8]. SOF4 has higher reactivity to amino functional groups than hydroxyl groups, resulting in another form of hexavalent sulfur link. Combined with the high selectivity of phenolic hydroxyl groups by SO2F2 gas, orthogonal modification of the compound (Figure 6) can be achieved.
► Figure 6. Image source: Angew. Chem. Int. Ed. 2017, 56, 2903
In view of the importance of SuFEx reaction, biochemical reagent manufacturer and supplier Sigma-Aldrich has set up a special web page to sell commonly used raw material compound libraries [9]. The initial application of
SuFEx reaction
Sharpless team and other research groups discussed the application of this controllable link reaction in polymers, small molecules and biological molecules in several papers.
For example, Dong Jiajia, a researcher at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, worked with the team of the Scripps Institute and Suzhou University to find that a class of anionic fluorine salt [HF2]- can serve as an efficient catalyst to further promote the SuFEx reaction and synthesize polysulfate or polysulfonate polymer material (Figure 7) [10]. Compared with polycarbonate and polyester materials, the corresponding polysulfate and polysulfonate materials have higher chemical stability and excellent mechanical properties.
► Figure 7. Image source:
https://cen.acs.org/articles/95/i26/New-catalytic-route-polysulfates-polysulfonates.html.
Suzhou University Lu Jianmei team cooperated with Wu Peng's research team at the Institute of Scripps to prepare reactive polymer [11] through SuFEx reaction, and the surface hydrophilicity of can be adjusted by further modifying azobenzene (Figure 8). The existence of the -SO2F group does not affect the occurrence of polymerization reactions, and at the same time overcomes the problems of insufficient surface modification activity of traditional polymers and insufficient precision reactions.
► Figure 8. Image source: Chem. Eur. J. 2017, 23, 14712
Related reviews recently published by Jason Locklin, Department of Chemistry at the University of Georgia, summarized the application progress of SuFEx in the fields of new material synthesis and surface modification [12].
In terms of synthetic methodology, the ginger group of the Shanghai Institute of Organics used fluorosulphonyloxy (ArOSO2F) as the cheap substitute functional group [13] of trifluoromethanesulfonyl (ArOTf) , and achieved a high yield Suzuki coupling reaction (Figure 9) in the aqueous phase.
► Figure 9. Image source: Org. Lett. 2015, 17, 1942
"Polymers and SuFEx reactivity is an unexpected discovery, and the most interesting application may not be the field of materials," said Dong Jiajia, "The interesting application lies in the fact that small molecules and large molecules carrying this type of functional groups will be directly and highly selective in the living body, and are also determined by the structure of the molecule, and directly react with the interacting proteins."
For example, with the unique reactivity of SuFEx, it is possible to achieve a high selectivity link between small molecules and a large number of functionally unrelated proteins under complex systems. Dong Jiajia and Chen Wentao et al. reported that fluorosulphonyloxy can selectively label the lipid-binding protein in the protein family under physiological conditions [14]. This high chemoselectivity is due to the fact that the tyrosine site in the lipid-binding protein is affected by the nearby arginine side chain, and the nucleophilicity of the phenolic hydroxyl group is significantly improved, thus helping to smoothly link with arylsulfonyl fluoride (Figure 10) .
► Figure 10. Image source: J. Am. Chem. Soc. 2016, 138, 7353
SuFEx This special selectivity can not only be used to label proteins, but also has important significance for drug screening. Recently, a paper from the Scripps Institute explored the application of fluorosulphonyloxy in the "Inverse Drug Discovery" [15], which was jointly completed by the team of the institute's chemistry, chemical biology , structural biology and drug chemistry . Traditional drug screening usually requires detecting the interaction between a certain protein and a large number of small molecules. It takes a lot of time to separate and extract proteins. The anti-drug synthesis law is the opposite. It is expected to directly select proteins that have the ability to bind to small molecules from the cells or protein groups, and fluorosulphonyloxy is an ideal highly selective electrophilic functional group.
Sharpless and Dong Jiajia used a theory called "Fringe Acid Base Reactivity " to explain SuFEx's almost unsightly selectivity, and believed that this is a generalized click chemistry concept with exploratory significance [1]. Compared with the previous CuAAC generation click chemistry reaction, Dong Jiajia emphasized: "Although the design principle is consistent with the CuAAC reaction, the first generation click reaction is that most of the A functional group are stable, and when encountering catalytic conditions and functional group B will be linked orthogonally efficiently. The most powerful thing about SuFEx is that only A functional group is A, and B is uncertain, and it is determined by the system. The first generation reaction is the highest reactivity representative of A+B, and how the second generation click chemistry SuFEx implements the A+ system." In other words, "CuAAC is a research tool, while SuFEx is more like a discovery tool."
Expo
Expectation
Expectation
00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000 Peter Gorlitz, former editor-in-chief of German Applied Chemistry, regarded Sharpless's first click chemistry paper published in 2001 as his favorite article [16], and the number of citations in this click chemistry foundation work has been nearly 10,000 times, far exceeding the reports on asymmetric epoxidation that won the Nobel Prize for Sharpless.
As a new click chemistry technology, although SuFEx reaction has just emerged, high-priced sulfur and fluorine compounds have also shown huge application prospects in the fields of Material Chemistry , chemical biology, biopharmaceuticals, etc., indicating that this field will rise rapidly and become one of the hot spots of click chemistry and fluorine chemistry.
References
[1] J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2014, 53, 9430
[2] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004.
[3] M. G. Finn, Chem. Soc. Rev. 2010, 39, 1231.
[4] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596.
[5] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057.
[6] T. Guo, G. Meng, X. Zhan, Q. Yang, T. Ma, L. Xu, K. B. Sharpless, J. Dong Angew. Chem. Int. Ed., DOI: 10.1002/anie.201711964, ASAP
[7] Professor Sharpless was hired as a distinguished professor at the Shanghai Institute of Organics in May 2016.
[8] S. Li, P. Wu, J. E. Moses, K. B. Sharpless, Angew. Chem. Int. Ed. 2017, 56, 2903.
[9] http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=111296651
[10] B. Gao, L. Zhang, Q. Zheng, F. Zhou, L. M. Klivansky, J. Lu, Y. Liu, J. Dong, P. Wu, K. B. Sharpless, Nature Chemistry 2017, 9, 1083.
[11] H. Zhu, D. Chen, N. Li, Q. Xu, H. Li, J. He, H. Wang, P. Wu, J. Lu, Chem. Eur. J. 2017, 23, 14712.
[12] J. Yatvin, K. Brooks, J. Locklin, Chem. Eur. J. 2016, 22, 16348.
[13] Q. Liang, P. Xing, Z. Huang, J. Dong, K. B. Sharpless, X. Li, B. Jiang, Org. Lett. 2015, 17, 1942.
[14] W. Chen, J. Dong, L. Plate, D. E. Mortenson, G. J. Brighty, S. Li, Y. Liu, A. Galmozzi, P. S. Lee, J. J. Hulce, B. F. Cravatt, E. Saez, E. T. Powers, Ian A. Wilson, K. Barry Sharpless, J. W. Kelly, J. Am. Chem. Soc. 2016, 138, 7353.
[15] D. E. Mortenson, G. J. Brighty, Lars Plate, Grant Bare, Wentao Chen, Suhua Li, Hua Wang, Benjamin F. Cravatt, Stefano Forli, Evan T. Powers, K. Barry Sharpless, Ian A. Wilson, and Jeffery W. Kelly J. Am. Chem. Soc., DOI: 10.1021/jacs.7b08366, ASAP
[16]https://cen.acs.org/articles/95/i48/German-journal-became-top-tier.html?utm_content=buffer6fad9&utm_medium=social&utm_source=linkedin.com&utm_campaign=buffer
Caroline Berthosi's biography: I guide my own chemistry genius
Caroline Berthosi
Caroline Berthosi (Carolyn R. Bertozzi) is a professor of chemistry, professor of chemistry and systems biology and radiology at Stanford University, a researcher at the Howard Hughes Institute of Medical Sciences, a member of the American Academy of Sciences, a member of the American Institute of Medical Sciences, and a member of the American Academy of Arts and Sciences. She graduated from Harvard University in 1988 and received her PhD in chemistry from the University of California, Berkeley in 1993. It is worth mentioning that in the last two or three years of his graduate school, because his supervisor was sick, Bertosi actually directed his own doctoral research. In 1996, she established her own research group at the University of California, Berkeley, began independent research, and won the MacArthur Genius Award in 1999 and the Wolf Chemistry Award in 2022.
In 2015, her research team moved to Stanford University. Bertosi's research interests are extensive and involve various aspects such as chemistry and biology, but the current research focuses on glycosylation of the cell surface during lesions, including different glycosylation reactions produced during cancer, inflammation and infection to assist in the diagnosis, prevention and treatment of diseases through research.
Caroline Bertosi won the Nobel Prize in Chemistry, which is closely related to her contribution to carbohydrates.Interestingly, Caroline was able to enter Harvard University mainly because she played well in football. However, this woman discovered that chemistry is her true love, and she guided herself to make her debut in the chemistry world when the authority in the chemistry world is not optimistic about girls and her mentor is sick.
Written by | Tan Zhongping Li Yaohao
Football player was well and was admitted to Harvard
Caroline was born in 1966 in Lexington, Massachusetts, northeastern United States . Her grandparents fled from Italy to the United States during the Mussolini government, while her grandparents immigrated from Canada to the United States during the Great Depression in the 1930s.
Her parents' encounter and know each other more in line with the traditional routine. At that time, her father was a professor in the Department of Physics at MIT and her mother was the secretary of the department. She met naturally. Her parents are said to be more traditional, such as building their own houses, wanting to have a boy, believing in the creed that one must have a skill to support the family, and hope that the son will inherit his father's business.
Of course, they didn't get exactly what they wanted, and only gave birth to three daughters. The three daughters didn't want to go to MIT to study physics as they wished. My elder sister Andrea Bertozzi (Andrea Bertozzi) chose to study for her PhD at Princeton University, and later became a professor of mathematics at Duke University (Duke) , and is now a professor at the University of Los Angeles, California (UCLA) . As the second child, Caroline chose Harvard University, a neighbor of MIT. Her youngest sister was even more rebellious and directly chose to let herself go in her studies.
One of the reasons why Harvard University admitted Caroline is that she played well in football, and she has great achievements in music. However, she finally listened to her parents and chose a biology major that could support her family in the future. The reason for choosing this major at that time was very simple. A biology teacher in high school gave a good lecture, which made her think biology was very interesting. However, after studying organic chemistry in the second year of undergraduate, she still found that organic chemistry was her favorite, so chemistry became her undergraduate major.
After entering Harvard University, Caroline began her scientific career as a god-assisted student. From 1987 to the present, she has received about 60 well-known scholarships, awards or honorary titles. If she had to say that there were setbacks, she had only two interesting small setbacks. One of them comes from Harvard University. When Caroline was studying for her undergraduate degree, it was the heyday of the development of all organic synthesis in the United States, and the organic synthesis of Harvard's Department of Chemistry was the world's leader. Caroline really wanted to join Harvard's organic synthesis laboratory for undergraduate research, but what frustrated her was that those authorities in organic synthesis did not recruit girls.
Just in time there is an assistant professor in physical and organic chemistry, Joseph Grabowski, (Joseph Grabowski), . Because of the serious lack of manpower, Caroline was invited to join his lab for his undergraduate thesis. It was also a blessing in disguise. Because the tutor had enough time to guide her, her thesis unexpectedly won the Thomas T. Hoopes Undergraduate Paper Award.
During her graduate school, Caroline still wanted to do organic synthesis, so she chose to study at the University of California, Burke, which is not so conservative in the Western Greater Bay Area of the United States. Here, she not only came into contact with organic synthesis, but also for the first time, and was exposed to almost all the key elements in her scientific research in the future, such as overlapping groups (Azide) , linking molecules (Linker) , and chemical sugar biology.These elements are mainly derived from her supervisor Mark D. Bednarski (Mark D. Bednarski), and the formation of her supervisor's research ideas may be related to her own experience: his PhD was obtained in the Yale lab of sugar synthesis master Samuel Danishevsky (Samuel J. Danishefsky), and the postdoctoral research was conducted in the laboratory of George Whitessets (George M. Whitesides) at Harvard University. When Caroline joined his lab, he had just started research independently for a year.
Caroline mainly uses synthesis in Berkeley to make probes or ligand molecules by connecting monosaccharides with non-natural carbon atoms to study their inhibitory effects on microorganisms. While studying carbon linking monosaccharide molecules, she also encountered a second small setback. In the third year of graduate school, her supervisor was unable to give normal guidance to the laboratory for the whole year due to the treatment of colon cancer. In his fourth year of graduate school, the supervisor chose to leave Berkeley and go to Stanford School of Medicine to start his own doctorate in medicine.
Of course, this small setback did not cause great obstacles to Caroline. She began to self-guid herself to do research, write articles, and apply for funds. She published six articles by the first author in the fourth grade of graduate student. Then she graduated in 1993 and successfully applied for a postdoctoral fellowship from the American Cancer Society. She moved from chemistry to biology, following Professor Steven D. Rosen from the University of California, San Francisco to explore and determine the structural characteristics of L-selectin substrates. Through collaboration with Professor (Laura L. Kiessling), they found that sugars specifically bound to L-selectin are a common structure, and their particularity is that the sugar carries a sulfate group on the 6-position hydroxyl group.
Proposing and advancing chemical sugar biology
Postdoctoral fellow just worked for a year and a half, and Caroline applied for an assistant professor at Stanford, Berkeley and San Francisco at the suggestion of a friend, and was successfully admitted to three prestigious schools. Finally, she chose to join her graduate school alma mater Berkeley in 1996.
Caroline's academic journey in Berkeley was also extremely smooth. She became an associate professor in 1999 and a professor in 2002. In these short six years, she has won academic awards that most people will never receive in their lifetime: a total of 23 awards were won in six years, including the 1999 MacArthur "Genius Award" (McArthur Foundation Award) . She was only 33 when she won the award and was the youngest winner at the time. She also became the coveted researcher of the Howard Dehughes Medical Institute, the Howard Dehugs Medical Research Institute, in 2000, and has maintained it to this day. This title means a large amount of scientific research funding support every year. A year later, in 2003, she became a member of the American Academy of Arts and Sciences (AAAS) . In 2005, she became a member of the American National Academy of Sciences (NAS) . The rewards of
are mainly due to Caroline's rapid outstanding achievements in sugar modification on the cell surface. Just one year after working independently, she used her knowledge in cell biology and chemistry to publish an innovative article on ( Science) . In this article, she used non-natural monosaccharides to induce cells to introduce carbonyl-containing sialic acid, carbonyl and hydrazine into the sugars expressed on their surface, and makes selective modification of sugar molecules on the cell surface possible. In addition to better imaging, labeling, mass spectrometry quantification and glycomic analysis of sugar molecules, this modification technology also provides available tools for the research and development of treatments for diseases such as infection, inflammation and cancer.
In the more than ten years after the article was published, Caroline's research focused on this research result.In 2003, she invented a new term, bioorthogonal chemistry (Bioorthogonal chemistry) , to describe this type of research method she used. Bioorthogonal chemistry, simply put, is the chemistry that can allow exogenous molecules or functional groups to react quickly and efficiently in complex environments in the organism, without affecting the normal reaction between molecules in the organism. It is one of the most important research that made Caroline famous quickly and one of the hottest jobs that made her a Nobel Prize Prophecy every year.
Although the carbonyl group was the first functional group used by Caroline in bioorthogonal chemistry, this functional group has a big defect, that is, the carbonyl group carried on many metabolites will have great interference to research. If Caroline likes most in scientific research, the azide group should be the top one. She has been using azide groups frequently since her graduate school. It is not difficult to understand why she quickly shifted her attention to the azide group.
The earliest bioorthogonal reaction based on azide functional groups developed by Caroline was the Staudinger coupling reaction (Staudinger ligation) used in 2000. This coupling reaction is achieved by forming an amide bond with azide with a specially designed triarylphosphine. The reaction is highly selective, but the phosphine molecules are easily oxidized and the reaction speed is relatively slow. These shortcomings affect the better application of this reaction.
After 2001 Nobel Prize winner Barry Sharpless (K. Barry Sharpless) reported a click chemical reaction between azide groups and terminal alkynyl groups catalyzed by copper ions, many laboratories began to try to use this more efficient bioorthogonal reaction to label and study biomolecules. However, due to the toxicity of copper ions, click chemistry is highly restricted in cells or living organisms. Therefore, people began to try to make copper-free modifications to click chemistry.
Starting in 2004, Caroline gradually developed a widely used improved version of copper-free click chemistry. The reaction uses azide groups and fluorocyclooctyrene with a large ring tension. The use of ring tension significantly accelerates the rate of reaction, bringing it very close to the rate of copper catalysis.
It is precisely because of the continuous development of these optimized chemical reactions that after the introduction of bioorthogonal chemistry, it has become a common method for in vivo and in vitro labeling, imaging and omics analysis of various molecules, cells, tissues, organs, etc. at an irresistible rate.
The late last century and the early this century were a climax of the development of sugar chemistry and biology. Summarizing her own experience and the research of many others, in 2001, Caroline and her postdoctoral collaborator Laura Kisling published a forward-looking review article in Science, which proposed the concept of "chemical sugar biology". The content of chemical sugar biology mainly includes the use of synthetic natural sugars, sugar analogs or sugar complexes for basic research on the properties, structure, function, metabolism, distribution, etc. of sugar, as well as the use of these molecules for application research on the development of new diagnostic methods, inhibitors, drugs and materials. In essence, it can be considered a projection and branching of chemical biology in the research direction of sugars represented by Peter Schultz (Peter G. Schultz) and Stuart Schreiber (Stuart L. Schreiber) in the early 1990s. In terms of heritage, Caroline happened to be a colleague who joined Berkeley ten years later than Peter, and Laura was Stuart's doctoral student at Yale and Peter's junior sister at Caltech.
Application research of chemical sugar biology
Caroline's scientific research can be simply based on 2008. In the past decade, she mainly focused on basic research. In the next ten years, her research gradually began to tilt towards application. The most obvious manifestation of this trend is that from 2008 to the present, she has established 7 biotechnology companies engaged in disease treatment and diagnosis research and development, 5 of which were established after she transferred to Stanford University in 2015. Of course, these companies are rooted in Caroline's research experience in sugar biology.
's courageous advance in the industry has not delayed Caroline's success in the academic world. In recent years, she has been a sensible figure in the field of sugar science, and her research results have been continuously appearing in scientific and technological news in countries around the world. Before winning the Wolf Chemistry Prize, her name last appeared on the news page at about half a year, which was about May last year. At that time, she published a sensational report in the magazine "Cell" (Cell) . Their research results pointed to an astonishing discovery that sugar modifications may also exist on ribonucleic acid (RNA) .
Before this report, people have been discovering sugar modifications of two other important biomolecular proteins and lipids for decades and have become very familiar. People have also known that sugar's modification of these two types of molecules is another important way for them to play a regulatory role in life activities by providing energy to play a regulatory role.
However, perhaps because ribose is also a sugar, no one has paid special attention to the combination of sugar and ribonucleic acid. This is the main reason why Caroline and others quickly caused a craze of discussion in the international scientific community after reporting this amazing and interesting discovery. Of course, it is undeniable that there are many unsolved important mysteries in this unexpectedly opened up new research direction, such as the structure, connection method, biosynthesis mechanism and the role of sugar, which may still require many years of more in-depth experiments to be revealed one by one. Although this discovery reported by Caroline in 2021 was very unexpected, the research method they used was still a research method based on azide-based sugaromics that they developed many years ago and have been using to this day.
In addition to preferring to use azide groups for research on sugar biology, Caroline also has a unique desire to use the linking molecule (Linker) . This scientific research habit also began during the postgraduate period. A more representative immunotherapy-related achievement she recently reported was achieved using linking molecules. In this research work, the role of the linking molecule is to couple with sialidase to the anti-human epidermal growth factor receptor 2 antibody (HER2 antibody trastuzumab) with sialidase. The design of the molecule of this structure facilitates the removal of sialic acid (Sialic acid) on the surface of tumor cells. Excessive sialic acid can form a protection on the surface of tumor cells, which inhibits its immune recognition. After trastuzumab binds to HER2, sialidases linked to the ligation molecule can selectively remove sialic acid from the surface of HER2+ breast cancer cells, allowing immune cells to kill these tumor cells more effectively through antibody-dependent cytotoxicity (ADCC) .
Using a similar strategy, Caroline has recently begun the development of new protein degradation technologies.In an article published in the journal Nature
in 2020, they reported a new technology based on the degradation of proteins through the lysosome degradation pathway, lysosome-targeting chimera technology (LYTAC, Lysosome-targeting chimaeras) . This new technology can solve the difficult problem of selective degradation of proteins secreted to extracellular and cell membranes in previous technologies.
In this work, they cleverly used the mannose-6-phosphate receptor (CI-M6PR, mannose-6-phosphate receptor) and specific antibodies connected with mannose-6-phosphate (M6P, mannose 6-phosphate) to transport proteins to the lysosomes for degradation. After the specific antibody binds the protein to be degraded, the protein to be degraded is brought into the lysosome through the binding of M6P and CI-M6PR. In lysosomes, secreted proteins and membrane proteins are targeted to degrade, while CI-M6PR can be recycled to the cell surface again.
This innovative work of organically combining biological and chemical is the focus of Caroline's research. These studies can not only help reveal the important role of sugar in biology and immunology, but also help achieve the important role of sugar in disease diagnosis and treatment. For example, HER2-targeted sialidase has become an important one in the pipeline of Palleon Pharmaceuticals, which she founded in 2015, and lysosome-targeted chimera technology has become the research and development platform technology of (Lycia Therapeutics) , which she founded in 2019.
In addition to these well-known research directions, Caroline has made great achievements in several other directions over the past 20 years, such as the sulfation modification of sugar, the direction of mycobacterial sugar science, the direction of enzyme small molecule inhibitors, and the direction of nanomaterials. It can freely gallop in these very different research directions, which is closely related to Caroline's cross-education and research background in biology and chemistry. The combination of biology and chemistry has also gradually proven to be an efficient sugar science research strategy.
"Sugar science is currently a new field full of unknowns and a niche field that many graduate students are unwilling to enter. As a researcher who has been exploring this field for many years, we are very happy to see that Caroline's work can be recognized by the Wolf Chemistry Prize. This recognition will play an important role in promoting the future development of sugar science." Professor Huang Xuefei, an internationally renowned sugar scientist, former chairman of the Sugar Branch of the American Chemical Society, commented, "Caroline has played an important role for many years, whether in scientific research or in other aspects. The methods she developed greatly facilitated the research and application of sugar; the direction she led pointed out the scientific research path for many young scientists who have entered the industry; her personal charm and passion also helped to cultivate and attract many people to the field of sugar science."
References:
. https://wolffund.org.il/
. https://digital.sciencehistory.org/works/3xomins
. https://bertozzigroup.stanford.edu
. Carolyn Bertozzi's glycocorevolution, Chem. Eng. News, 2020, Volume 98, Issue 5.
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