Ye Xinshan's team has made a major breakthrough in the field of automatic sugar synthesis

On September 29, 2022, Ye Xinshan's research team at the State Key Laboratory of Natural and Biomimetic Drugs at the School of Pharmacy of Peking University published an online report entitled "Automated solution-phase multiplicative synthesis of complex glycans up to a" in Nature Synthesis 1,080-mer) research paper reporting on breakthroughs in the field of carbohydrate synthesis
.
Based on the principle of "pre-activation" multi-component glycosylation reaction and liquid phase multiplication synthesis, the team independently developed a new dual-mode liquid sugar automatic synthesis instrument; And the use of the automatic synthesis instrument synthesized a variety of complex structures of oligosaccharides and polysaccharides, of which the molecular size of the synthesized polysaccharides reached an astonishing 1080 sugars (1080-mer), the synthesis of structurally homogeneous polysaccharide molecules to a new height, far beyond the synthesis level
of nucleic acids (to 200-mer) and proteins (to 472-mer).
Given the significance of this achievement in the synthesis of macromolecules and their applications, the journal Nature has published a brilliant review of this work
.

Carbohydrates are ubiquitous in nature and are involved in almost all life processes of multicellular organisms, such as fertilization, implantation, differentiation, development, immunity, infection, cancer, aging, and so on
.
Due to the inherent complexity of the structure of carbohydrates, in order to obtain well-structured, uniform glycan compounds, synthesis is difficult, often requiring highly specialized personnel to complete through manual synthesis, time-consuming and laborious, which seriously restricts the development of sugar science; The synthesis of polysaccharides with larger molecular sizes and more complex structures is an extremely challenging task
.
At present, the development of automatic synthesis technology of carbohydrate compounds in the world is still in its infancy, especially the development of liquid sugar automatic synthesis instruments is basically blank at home and abroad, so the synthesis paradigm of carbohydrate compounds needs to be changed
.

Ye Xinshan's team developed a one-pot continuous oligosaccharide synthesis strategy based on the "pre-activation" of glycosyl donors in the early stage, thus laying the foundation
for the development of automatic sugar synthesis instrument.
The hardware of the synthesizer includes automatic synthesis system (including automatic injection system and synthesis assistance system), online monitoring system and programmable logic control system, and the automatic synthesis system and the online monitoring system are coupled through the programmable logic control system, and the whole machine framework of the new dual-mode liquid sugar automatic synthesis instrument is successfully designed, and the smooth assembly
of the first generation of prototypes is realized 。 In terms of software, the programmable logic control system is controlled by the host computer, and based on the Labview language program design, the practical feature host computer software control system (Ye Glycosoft) has been developed to complete the whole machine control and debugging of the synthesizer, and the stable operation
of the synthesizer is realized.

In order to verify the function of the developed synthesizer, they used the synthesizer to carry out the following work: (1) in the ordinary activation mode or light-mediated activation mode, the library of oligosaccharide compounds with important biological activity, including various glycoforms and glycosidic bond connection methods, was quickly and automatically synthesized; (2) Automatic synthesis of anticoagulant glycemic drug fonda hepatic sunflower sodium pentaglycoride with protective group at the scale of gram scale and high yield; (3) Using monosaccharides as raw materials, the automatic coupling reaction of ten components in a kettle was successfully realized to obtain polyarabinosaccharides; On this basis, the polysaccharide arabinagan composed of 1080 monosaccharide units is automatically synthesized by using the automatic multiplication synthesis strategy, and arabinosan is an important component
of the cell wall of plants and pathogenic bacteria.
This is the largest and longest polysaccharide molecule currently synthesized, making the number of monomer composition representing the complexity of synthetic homogeneous structure biological macromolecules reach the four-digit level for the first time, which is of important milestone significance
in the field of polysaccharide synthesis.
The synthesizer provides a platform for non-professionals to assemble target glycans, fills the gap in the development of liquid sugar synthesizers at home and abroad, and will provide new and effective tools
for glycoscience and its application in the field of medicine and materials.

Yao Wenlong, a postdoctoral fellow at Peking University School of Pharmacy, is the first author of the research paper, and Professor Ye Xinshan is the corresponding author of the paper.
Researcher Xiong Decai and some graduate students of Ye Xinshan's team participated in the research work
.
The research work has been funded
by the National Key Research and Development Program, the National Natural Science Foundation of China, the State Key Laboratory Instrument Development and other projects.

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【About the Author】

Yao Wenlong, Ph.
D.
of 2016 and Postdoctoral Fellow of 2020, School of Pharmacy, Peking University
.
His research interests include sugar chemistry, sugar pharmaceuticals, and the automation and intelligence of chemical synthesis, and has been developed in Nat.
Synth、J.
Am.
Chem.
Soc.
and other journals have published 5 academic papers, applied for 7 patents, obtained 4 authorized patents, and presided over 1 national natural youth fund
.

Ye Xinshan is a professor and doctoral supervisor of the School of Pharmacy of Peking University, the deputy dean of the School of Pharmacy of Peking University, and the winner of
the National Outstanding Youth Science Foundation.
Engaged in the research of glycochemistry, glycopharmaceutical chemistry and glycochemical biology, he has published more than 180 papers and 17 authorized invention patents
.
Some of his achievements have won the second prize of the National Natural Science Award, the first prize of Science and Technology of the Chinese Pharmaceutical Association, the 13th Wu Jieping-Paul Janssen Medical Pharmacy Award, and the Zhang Shuzheng Sugar Science Outstanding Achievement Award
.
He currently serves as the deputy editor of Chinese Chemical Letters, the executive editor of the Journal of Chinese Pharmaceutical Sciences, and the chairman of the Sugar and Vaccine Professional Committee of the Chinese Vaccine Industry Association and the vice chairman of the Glycochemistry Professional Committee of the Chinese Chemical Society
.

State Key Laboratory of Natural and Biomimetic Drugs Contributed by the State Key Laboratory of Natural and Biomimetic Drugs