Recent advances on the one-pot synthesis to assemble size-controlled glycans and glycoconjugates and polysaccharides
Introduction
Carbohydrates, the most abundant class of natural products, are polyhydroxyl aldehydes or polyhydroxyl ketones and their polycondensates and derivatives (Zhang & Ye, 2018). As one of the important class of biological macromolecules, polysaccharides are ubiquitously distributed in nature, present in all living organisms, including animals, plants and microbes (Liu, Willför, & Xu, 2015; Lovegrove et al., 2017; Qin et al., 2019). Moreover, carbohydrates are usually bound to lipids or proteins to form glycoconjugates such as glycolipids, glycoproteins and proteoglycans (Colombo, Pitirollo, & Lay, 2018; Lin, Qiao, Zhang, & Linhardt, 2020). These glycans and glycoconjugates play many critical roles, eliciting a myriad of key biological processes, involving viral and bacterial infection, cell signaling, cell proliferation and differentiation, angiogenesis and metastasis, immune-responses, and neurodegenerative diseases (Boltje, Buskas, & Boons, 2009; Ji, Li et al., 2020; Varki, 1993, 2017). For example, cell-surface glycans directly participate in a wide variety of biological recognition processes including cell adhesion, signaling, development, and the immune response (Dwek, 1996; Haltiwanger & Lowe, 2004; Jefferis, 2009; Macauley, Crocker, & Paulson, 2014; Nimmerjahn & Ravetch, 2008; Varki, 1993). SARS-CoV-2 infection has recently been reported to depend on cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2), suggesting that exogenous heparin presents potential therapeutic opportunities (Clausen et al., 2020; Kwon et al., 2020).
Polysaccharides generally have two properties associated with their homogeneity. Structural homogeneity refers to the presence of a single repeating unit while molecular weight homogeneity refers to a polydispersity index of 1.0. Most naturally occurring glycans are usually structurally heterogeneous coming from limited sources and with high-cost production. For example, animal-sourced heparin is a widely used polydisperse anticoagulant drug, complicating detailed structure activity relationship studies, thus, hampering its other therapeutic applications (Li & Wang, 2018; Zhang, Lin, Huang, & Linhardt, 2020). In addition, polysaccharides having different molecular weights can possess different physiological and pharmacological functions (Table 1). High molecular weight hyaluronic acid (HMW-HA) has been applied by inhalation to clinically treat inflammation, while low molecular weight hyaluronic acid (LMW-HA) exhibits proinflammatory characteristics (Li, Qiao et al., 2020; Li, Yao et al., 2020). Moreover, impurities are inevitably present due to the incorporation of other similar polysaccharides and bioactive entities such as viruses, prions or growth-modulating factors in animal tissues (Liu & Linhardt, 2014). A crisis resulted from the worldwide distribution of contaminated heparin in 2007 highlighted the importance of developing homogeneous heparin drug instead of a heterogeneous one from an animal source (Guerrini et al., 2010; Szajek et al., 2016). Consequently, efficiently preparing homogeneous, or nearly homogeneous, polysaccharides or structurally well-defined oligosaccharides is at the forefront of the new-generation carbohydrate-based drug development, resulting in reproducible biological properties as well as a safer and more secure supply chain (Fig. 1).
Section snippets
General approaches for preparing homogeneous glycans
Generally, homogeneous glycans can be synthesized using three strategies: 1. degradation methods; 2. pure chemical synthesis assembly; and 3. enzymatic or chemoenzymatic synthesis assembly. These synthetic approaches hold their own characteristics and scopes of application, respectively, which are be described below (Table 2).
Techniques for structure characterization/quantification of glycans
Liquid chromatography (LC), gas chromatography (GC), nuclear magnetic resonance (NMR) and mass spectrometry (MS), etc., are common techniques in the structure analysis and quantification of polysaccharides and oligosaccharides. High performance liquid chromatography (HPLC) is widely used in the separation and purification of oligosaccharides, composition analysis, quantitative determination and molecular weight determination (Wang et al., 2018). GC is suitable for the analysis of volatile sugar
Controlling molar ratio of the donor and acceptor
As sugar nucleotide donors are transferred to glycosyl acceptors by glycosyltransferases or synthases in glycan biosynthetic pathways, controlling the molar ratio of the donor and acceptor may be the promising and simplest way to prepare size-controlled polysaccharides. Fang et al. successfully prepared homogeneous hyaluronic acid (HA) polymers taking HA oligosaccharides as the starting receptors catalyzed by P. multocida (PmHAS) in a combined manner, involving the stepwise enzyme-catalyzed
Conclusion and perspectives
In conclusion, in this review, we provide an overview of the synthetic strategies to obtain size-controllable or homogeneous glycans using a one-pot method. Although traditional chemical methods are still the major ways of preparing homogeneous oligosaccharides, problems such as lengthy steps, complicated purification operations and limited product size still exist. The one-pot method greatly simplifies the operation procedure and reduces the cost of preparing homogeneous polysaccharides. While
Acknowledgements
The authors were supported in part by grants from National Natural Science Foundation, China (22007049 to XZ and 22007048 to BS) and the National Institutes of Health (DK111958 and CA231074 to RJL).
References (77)
- et al.
Synthesis of lipopolysaccharide O-antigens by ABC transporter-dependent pathways
Carbohydrate Research
(2012) - et al.
O-antigen structural variation: Mechanisms and possible roles in animal/plant-microbe interactions
FEMS Microbiology Reviews
(2002) - et al.
Chemical, enzymatic and biological synthesis of hyaluronic acids
International Journal of Biological Macromolecules
(2020) - et al.
Total synthesis of tumor-associated KH-1 antigen core nonasaccharide via photo-induced glycosylation
Organic Chemistry Frontiers
(2020) - et al.
Site-selective reactions for the synthesis of glycoconjugates in polysaccharide vaccine development
Carbohydrate Polymers
(2020) - et al.
A review of bioactive plant polysaccharides: Biological activities, functionalization, and biomedical applications
Bioactive Carbohydrates and Dietary Fibre
(2015) - et al.
Graft copolymers prepared by atom transfer radical polymerization (ATRP) from cellulose
Polymer
(2009) - et al.
Production of chitin oligosaccharides with different molecular weights and their antioxidant effect in RAW 264.7 cells
Journal of Functional Foods
(2009) - et al.
Homogeneous synthesis of cellulose acrylate-g-poly (n-alkyl acrylate) solid-solid phase change materials via free radical polymerization
Carbohydrate Polymers
(2018) - et al.
Structural characterization and immunoregulatory activity of two polysaccharides from the rhizomes of Atractylodes lancea (Thunb.) DC
International Journal of Biological Macromolecules
(2019)
Chemoenzymatic synthesis of 4-Fluoro-N-acetylhexosamine uridine diphosphate donors: Chain terminators in glycosaminoglycan synthesis
The Journal of Organic Chemistry
Production of homogeneous glycoprotein with multisite modifications by an engineered N-glycosyltransferase mutant
The Journal of Biological Chemistry
Hyaluronan fragments: An information-rich system
European Journal of Cell Biology
Sequencing the oligosaccharide pool in the low molecular weight heparin dalteparin with offline HPLC and ESI-MS/MS
Carbohydrate Polymers
Facile chemoenzymatic synthesis of biotinylated heparosan hexasaccharide
Organic & Biomolecular Chemistry
One-pot multienzyme (OPME) systems for chemoenzymatic synthesis of carbohydrates
Organic & Biomolecular Chemistry
Enzymatic production of specifically distributed hyaluronan oligosaccharides
Carbohydrate Polymers
Fluorous technologies for solution-phase high-throughput organic synthesis
Tetrahedron
Chemoenzymatic synthesis of unmodified heparin oligosaccharides: Cleavage of p-nitrophenyl glucuronide by alkaline and Smith degradation
Organic & Biomolecular Chemistry
Study on different molecular weights of chitosan as an immobilization matrix for a glucose biosensor
PloS One
Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research
Nature Chemistry
Fluorous-assisted chemoenzymatic synthesis of heparan sulfate oligosaccharides
Organic Letters
Tailored design and synthesis of heparan sulfate oligosaccharide analogues using sequential one-pot multienzyme systems
Angewandte Chemie-International Edition
SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2
Cell
Recent advances in the synthesis of glycoconjugates for vaccine development
Molecules
Masquerading microbial pathogens: Capsular polysaccharides mimic host-tissue molecules
FEMS Microbiology Reviews
Chemoenzymatic synthesis of glycosaminoglycans: Re-creating, re-modeling and re-designing nature’s longest or most complex carbohydrate chains
Glycobiology
Glycobiology: Toward understanding the function of sugars
Chemical Reviews
Comparison of chitosans with different molecular weights as possible wood preservatives
Journal of Wood Science
A general strategy for the synthesis of homogeneous hyaluronan conjugates and their biological applications
Chemical Communications
Reduction of aryl halides by consecutive visible light-induced electron transfer processes
Science
Oversulfated chondroitin sulfate is the major contaminant in suspect heparin lots collected in February/March of 2008
Nature Biotechnology
Role of glycosylation in development
Annual Review of Biochemistry
Impact of water extractable arabinoxylan with different molecular weight on the gelatinization and retrogradation behavior of wheat starch
Food Chemistry
Glycosylation as a strategy to improve antibody-based therapeutics
Nature Reviews Drug Discovery
Advances on the in vivo and in vitro glycosylations of flavonoids
Applied Microbiology and Biotechnology
Synthesis of structurally defined chondroitin sulfate: Paving the way to the structure-activity relationship studies
Carbohydrate Polymers
Carbohydrate isomer systems examination by dynamic NMR-Spectroscopy
Deutsche Lebensmittel-Rundschau : Zeitschrift Fur Lebensmittelkunde Und Lebensmittelrecht
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These authors contributed equally.