CNS active O-linked glycopeptides.

Evan M Jones,Robin Polt

doi:10.3389/fchem.2015.00040

Abstract

Naturally occurring glycopeptides and glycoproteins play important roles in biological processes. Glycosylation is one of the most common post-translational modifications in vivo. Glycopeptides are involved in cell signaling and sorting, providing cell surface markers for recognition. From the drug design and synthesis perspective, modification of a peptide through glycosylation results in increased bioavailability and bioactivity of glycopeptides in living systems with negligible toxicity of degradation products. Glycopeptide synthesis can be accomplished through incorporation of a glycosylated amino acid in solid phase peptide synthesis (SPPS) to form the desired peptide, or via incorporation of sugar-amino acid moieties. Additionally, research indicates that glycosylation increases penetration of the blood-brain barrier (BBB) by peptides, which may lead to novel therapeutics for neurological disorders. Recent applications of glycopeptides have focused on the in vivo central nervous system (CNS) effects after peripheral administration of centrally active peptides modified with various carbohydrates.

Highlights

Derived peptides are attractive as a source of drugs due to their potent and highly selective interactions with G-protein coupled receptors (GPCRs), combined with their very low levels of toxicity (Kaspar and Reichert, 2013; Fosgerau and Hoffmann, 2015)
Glycopeptides play a wide range of roles in the regulation of many biochemical functions (Taylor, 1998)
While it was noted that different types of breast cancer each had different aberrations [for instance, purified MUC1 from T47D breast cancer cell lines has primarily core 1 type O-glycans, while MUC1 from MCF-7 is composed of core 2 type O-glycans (Muller and Hanisch, 2002)], all breast cancer cell lines displayed an increased number of carbohydrates per glycoprotein when compared with healthy cells

Summary

Introduction

Derived peptides are attractive as a source of drugs due to their potent and highly selective interactions with G-protein coupled receptors (GPCRs), combined with their very low levels of toxicity (Kaspar and Reichert, 2013; Fosgerau and Hoffmann, 2015). Classical “small molecule” drugs are frequently promiscuous, leading to unpredicted off-target interactions as well as toxic metabolites (Rao and Mohamed, 2011). These same proteolysis pathways represent a challenge since many peptides exhibit serum half-lives of only a few minutes (Fosgerau and Hoffmann, 2015). One modification that has shown much promise in recent years is glycosylation: appending a carbohydrate moiety along the peptide backbone to form glycopeptides. Glycopeptides play a wide range of roles in the regulation of many biochemical functions (Taylor, 1998) These include cell signaling and immune system response (Rudd et al, 2001). While it was noted that different types of breast cancer each had different aberrations [for instance, purified MUC1 from T47D breast cancer cell lines has primarily core 1 type O-glycans, while MUC1 from MCF-7 is composed of core 2 type O-glycans (Muller and Hanisch, 2002)], all breast cancer cell lines displayed an increased number of carbohydrates per glycoprotein when compared with healthy cells

Benefits and Disadvantages of Carbohydrate Incorporation

Development and Applications of Neurologically Active Glycopeptides

Future Directions and Applications