Design and Synthesis of Neurologically Active Glycopeptides for Neuroprotection and Antinociception

Abstract

Endogenous peptides modulate a wide range of physiological conditions in the central and peripheral nervous systems, but have not been harnessed to perform similar functions in pharmaceutical roles due to their ease of degradation and difficulty in introducing into the neurovascular unit. We report herein advances that evidence the wide applicability that glycosylation provides as a pathway for improving the drug-like properties of peptides. This is demonstrated by utilizing novel sugar-amino acids to modify the potent mu opioid receptor agonist DAMGO to provide antinociception, and serine glycosides to modify secretin family peptides for neuroprotection and angiotensin-(1-7) to both reduce cognitive impedance following myocardial infarction and as a treatment for peripheral neuropathy. Evidence is presented via a series of in vitro and in vivo models and assays, and demonstrates the advantageous effects of glycosylation through increased persistence in serum, greatly improved blood-brain barrier penetration, and the tolerance of receptor interactions to the addition of a carbohydrate.