CNS active O-linked glycopeptides

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.

A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction

“…Synthesis of Peptides. Glycosylated peptides were synthesized by the Polt Laboratory (University of Arizona) via solid-phase synthesis, using methods previously described (Lowery et al, 2007;Jones and Polt, 2015;Lefever et al, 2015).…”

“…These agonists are designed to improve bioavailability, stability, and brain penetration of Ang-(1-7). Our research team has developed, optimized, and completed high-throughput in vitro and in vivo screens of novel synthetic glycopeptide derivatives of Ang-(1-7) that have outstanding brain penetration and enhanced stability (Dhanasekaran and Polt, 2005;Malakoutikhah et al, 2008;Jones and Polt, 2015). We have completed a full physiochemical and mechanistic preclinical study of the in vitro and in vivo behavioral properties of our lead candidate, Ang-1-6-O-Ser-Glc-NH 2 (PNA5).…”

Highly-selective μ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model

“…In order to investigate the anti-dyskinetic potential of specifically only blocking m-opioid receptors we conducted experiments in the standard rodent model of established LID, 6-hydroxydopamine (6-OHDA)-lesioned hemi-parkinsonian rats primed with L-DOPA, using the highly-selective m-opioid receptor antagonists CTAP (IC50=3.5 nM and >1,200-fold selective for m-over d-opioid receptors) [8] and a congener gCTAP5, that had been glycosylated to increase stability [9].…”

Highly-selective μ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model

“…In order to investigate the anti-dyskinetic potential of specifically only blocking ∝-opioid receptors we conducted experiments in the standard rodent model of established LID, 6-hydroxydopamine (6-OHDA)-lesioned hemi-parkinsonian rats primed with L-DOPA, using the highly-selective ∝-opioid receptor antagonists CTAP (IC50 = 3.5 nM and > 1,200-fold selective for ∝-over δ-opioid receptors) [8] and a congener gCTAP5, that had been glycosylated to increase stability [9].…”