An important goal of research activities in the Polt Group is to use endogenous peptide neurotransmitters as a starting point for drug design. Other researchers have identified both opioid and non-opioid peptides that are responsible for modulation of brain function. Moreover, the endogenous peptide sequences have been modified to achieve optimum binding and biological effects in many cases. However, the effectiveness of this approach has been very limited because it depends on successful transport across the blood-brain barrier (BBB). A breakthrough has now been achieved with the recognition that biousian glycopeptides can penetrate the BBB and other cellular barriers in vivo.

Thousands of man-years of work has now gone into the discovery and modification of endogenous opioid peptides over the past 30 years. None of these peptides penetrate the BBB well enough to allow for modification of brain function. However, incorporation of simple glycoside moieties has allowed the Polt Group to manipulate the amphipathic character of opioid peptides to achieve penetration of the BBB. Using enkephalin structures as a starting point, it has been possible to produce analgesic compounds with very different side effect profiles (see blue panels).

The antinociceptive effects (analgesic effects) of the glycosylated enkephalins MD-2200 (left) and LYM-147 (right) are measured in mice with the widely-used "tail flick" assay.

Relevant Publications

Enkephalin Glycopeptide Analogues Produce Analgesia with Reduced Dependence Liability. Bilsky et al, J. Med. Chem. 2000, 43, 2586-2590.

Biousian glycopeptides penetrate the blood-brain barrier. Egleton et al, Tetrahedron: Asymmetry 2005, 16, 65-75.

Improved Blood-Brain Barrier Penetration and Enhanced Analgesia of an Opioid Peptide by Glycosylation Egleton et al, J. Pharmacol. Exp. Ther. 2001, 299, 3, 967-972.

Solid-Phase Synthesis of O-Linked Glycopeptide Analogues of Enkephalin Mitchell et al, J. Org. Chem. 2001, 66, 2327-2342.

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides Elmagbari et al., J. Pharmacol. Exp. Ther. 2004, 311, 1, 290-297.

A UNE researcher aims for a painkiller like morphine, minus the side effects Portland Press Herald February 27, 2005.

Glycopeptides Related to β-Endorphin Adopt Helical Amphipathic Conformations in the Presence of Lipid Bilayers Dhanasekaran et al., J. Am. Chem. Soc. 2005 127, 5435-5448.