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GlycopeptideGlycopeptide is a compound obtained by connecting a short sugar chain with a short peptide.A large number of glycopeptides have been found in animals, plants and microorganisms.[1]
There are two main types of glycopeptide bonding: N –Glycopeptide bondO – glycopeptide bond.
1、 N – glycopeptide bond, referring toβ–N-acetylglucosamine isomer carbon of configuration andAsparagineOfγ–N-glycoside bond formed by covalent linkage of N atoms of amide.
2、 O – glycopeptide bond refers to the O – glycoside bond formed by covalent combination of heterocyclic carbon of monosaccharide and hydroxyl O atom of hydroxyamino acid.
application development
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Glycopeptide is a kind of macromolecular compound combining oligosaccharide and polypeptide.
Glycopeptides have important applications in the research and development of carbohydrate drugs, such as glycopeptide antibiotics and anti-tumor vaccines.After decades of development, peptide synthesis technology has been very mature, and oligosaccharide synthesis has also made progress in recent years.However, the synthesis of glycopeptides is still a challenging problem.[1]
chemical synthesis
In September 2020, the research team of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, cooperated with Professor Wang Peng of South University of Science and Technology to complete the communication paper and published it online onAngew.Chem.Int.Ed.On.[1]
This study reported the synthesis of glycopeptides with complex oligosaccharide structure (Proof of Concept) by commercial peptide synthesis apparatus and chemical enzymatic synthesis strategy.
In this study, researchers found a silicon ball with aminated surface by screening a large number of solid phase carriers that can be used for solid phase synthesis. It can be used for peptide chain synthesis in organic phase and oligosaccharide synthesis in aqueous phase (enzyme reaction) at the same time.This kind of silicon ball only has amino groups on its surface, so the researchers designed a breakable linker to connect the silicon ball resin with the starting amino acid.Although the loading efficiency of the silica sphere resin is lower than that of the commonly used solid phase resin for peptide synthesis, it can simultaneously support the peptide synthesis reaction in the organic phase and the enzymatic reaction in the aqueous phase.[1]
Based on this, researchers have developed a two-phase reaction system for the technical platform of glycopeptide synthesis in combination with a commercial peptide synthesizer.The resin loaded with the initial amino acid is added to the reactor in advance, and then the synthesizer automatically adds the next amino acid and the condensation reagent (deprotection reagent) to the reactor. After the reaction is completed, the rest of the reagents are pressurized and filtered, which completes a cycle.
By setting the reaction program, the corresponding amino acids can be cyclically reacted in turn, and the target peptide chain can be obtained after multiple cycles.Then the system is switched to the aqueous phase, and different glycosyltransferases and corresponding glycosides are subjected to the same cyclic reaction in turn (reaction temperature is 37 ℃). After several cycles, the target glycopeptide can be obtained, and then the glycopeptide is eluted from the resin.
The glycopeptide synthesis platform is simple and easy to operate. Based on the commercial peptide synthesis instrument, 13 complex glycopeptides (10 tumor markers MUC1 glycopeptides and three HIV glycopeptides) have been semi automatically synthesized.[1]
Drug development
At present, antimicrobial agents for gram-positive bacteria have achieved good results, especially the development of the second generation of glycopeptide antibiotics (GPAs) - Oritavanin and Dalbavanin. However, in the face of the inevitable resistance of glycopeptide antibiotics, it is still necessary to develop new GPAs.[2]
In 187 traditional antibacterial agent projects developed clinically at the end of 2019, a small part of the research（n=35, 19%) are improved derivatives of known antibiotics (old targets), includingβ–Other inhibitors of lactams – penicillin binding proteins, fluoroquinolones – new bacterial topoisomerase inhibitors, aminoglycosides, polymyxin and macrolides;Most projects（n=135, 72%) focused on new target research, including synthetic and natural antimicrobial peptides (AMPs), natural products and LpxC inhibitors;On this basis, almost half of the projects mainly target gram-negative bacteria, and only about 10% of the projects target gram-positive bacteria (mainly Staphylococcus).
At present, the drugs used to treat gram-positive bacterial infections include glycopeptides (inhibiting the synthesis of peptidoglycans by combining with lipid II: vancomycin, teicoplanin, and teravancin, orivancin, and dabavan), lipopeptides (destroying cell membranes: datomicin), oxazolidones (inhibiting the synthesis of proteins: linezolid and terdazolomide)Cephalosporins (inhibiting the synthesis of peptidoglycans by binding to penicillin binding proteins: the fifth generation of cefalolin and cefepip) and glycyltetracycline (inhibiting the synthesis of proteins: tegacycline).[2]
