Chemical Glycosylation and Its Application to Glucose Homeostasis-Regulating Peptides

Abstract

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.

Better Peptides via Chemical Glycosylation: Somatostatin Analogues Having a Human Complex‐Type N‐Glycan with Improved Drug Properties

“…Glycan chains are considered to possess an ability to shield and/or reduce the biological degradation and neutralization in the blood of peptides/proteins to which they are conjugated [21] . This implies that the presence of glycans may affect serum half‐life and clearance and may be involved in regulating the immunogenic properties of glycosylated peptides and proteins [22] .…”

Ca2+-Responsive Glyco-insulin

“…Glycosylation of therapeutic peptides and proteins is known to improve the pharmacodynamic and pharmacokinetic profile, often without leading to immunogenicity. − Furthermore, the hydrophilic nature of glycans can increase the solubility and prevent aggregation . The improvement of the serum half-life of insulin has also been achieved through sialic acid conjugation .…”

“…28−30 Furthermore, the hydrophilic nature of glycans can increase the solubility and prevent aggregation. 31 The improvement of the serum half-life of insulin has also been achieved through sialic acid conjugation. 32 Sialylated insulin was obtained using enzymatic or chemical methods and had excellent stability at high temperatures.…”

Discovery and biosynthesis of persiathiacins: Unusual polyglycosylated thiopeptides active against multi-drug resistant tuberculosis

“…Glycosylation of the hydroxypyridine in nocathiacin has been reported to significantly improve aqueous solubility and, more generally, glycosylation is a widely used strategy for increasing the solubility and circulatory half-life of therapeutic peptides. [19][20][21] Thus, the discovery of the persiathiacins and the gene cluster directing their biosynthesis provides new opportunities for the development of biosynthetic engineering strategies for the creation of novel (poly)glycosylated thiopeptides with improved pharmacological properties.…”