Chemical Glycosylation and Its Application to Glucose Homeostasis-Regulating Peptides

Peptides and proteins are attractive targets for therapeutic drug development due to their exquisite target specificity and low toxicity profiles. However, their complex structures give rise to several challenges including solubility, stability, aggregation, low bioavailability, and poor pharmacokinetics. Numerous chemical strategies to address these have been developed including the introduction of several natural and non-natural modifications such as glycosylation, lipidation, cyclization and PEGylation. Glycosylation is considered to be one of the most useful modifications as it is known to contribute to increasing the stability, to improve solubility, and increase the circulating half-lifves of these biomolecules. However, cellular glycosylation is a highly complex process that generally results in heterogenous glycan structures which confounds quality control and chemical and biological assays. For this reason, much effort has been expended on the development of chemical methods, including by solid phase peptide synthesis or chemoenzymatic processes, to enable the acquisition of homogenous glycopeptides to greatly expand possibilities in drug development. In this mini-review, we highlight the importance of such chemical glycosylation methods for improving the biophysical properties of naturally non-glycosylated peptides as applied to the therapeutically essential insulin and related peptides that are used in the treatment of diabetes.

Characterization of Glycosyl Dioxolenium Ions and Their Role in Glycosylation Reactions

Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-<i>trans</i> glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-<i>cis</i> linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT calculations and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research

Characterization of Glycosyl Dioxolenium Ions and Their Role in Glycosylation Reactions

Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-<i>trans</i> glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-<i>cis</i> linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT calculations and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research

A Solution to Chemical Pseudaminylation via Development of a Bimodal Glycosyl Donor to Enable Highly Stereocontrolled α- and β-Glycosylation

Bacterial pseudaminic acids (Pse) are present on the surface of many pathogenic bacteria. Herein, we report a robust methodology for the stereocontrolled chemical glycosylation of pseudaminic acid to afford both α- (axial) and β- (equatorial) glycosides reliably with complete stereoselectivity, using a common glycosyl donor (7<i>N-</i>Cbz/5<i>N</i>-azido Pse thioglycoside) simply by changing the reaction conditions (DCM-DMF, -40 ^oC and DCM/MeCN, -78 ^oC, respectively). Examples of such bimodal selectivity are both sparse and highly sought-after in carbohydrate chemistry. This method enables efficient access to pseudaminylated molecules, which will open up various opportunities in chemical glycobiology research of bacterial pseudaminic acids and carbohydrate-based antibacterial vaccine development.

A Solution to Chemical Pseudaminylation via Development of a Bimodal Glycosyl Donor to Enable Highly Stereocontrolled α- and β-Glycosylation

Bacterial pseudaminic acids (Pse) are present on the surface of many pathogenic bacteria. Herein, we report a robust methodology for the stereocontrolled chemical glycosylation of pseudaminic acid to afford both α- (axial) and β- (equatorial) glycosides reliably with complete stereoselectivity, using a common glycosyl donor (7<i>N-</i>Cbz/5<i>N</i>-azido Pse thioglycoside) simply by changing the reaction conditions (DCM-DMF, -40 ^oC and DCM/MeCN, -78 ^oC, respectively). Examples of such bimodal selectivity are both sparse and highly sought-after in carbohydrate chemistry. This method enables efficient access to pseudaminylated molecules, which will open up various opportunities in chemical glycobiology research of bacterial pseudaminic acids and carbohydrate-based antibacterial vaccine development.