Glycosylated neuropeptides: A new vista for neuropsychopharmacology?

Abstract

The application of endogenous neuropeptides (e.g., enkephalins) as analgesics has been retarded by their poor stability in vivo and by their inability to effectively penetrate the blood-brain barrier (BBB). Effective BBB transport of glycosylated enkephalins has been demonstrated in several labs now. Analgesia (antinociception) levels greater than morphine, and with reduced side effects have been observed for several glycopeptides related to enkephalin. Somewhat paradoxically, enhanced BBB transport across this lipophilic barrier is achieved by attaching water-soluble carbohydrate groups to the peptide moieties to produce biousian glycopeptides that can be either water-soluble or membrane bound. Transport is believed to rely on an endocytotic mechanism (transcytosis), and allows for systemic delivery and transport of the water-soluble glycopeptides. Much larger endorphin/dynorphin glycopeptide analogs bearing amphipathic helix address regions also have been shown to penetrate the BBB in mice. This holds forth the possibility of transporting much larger neuropeptides across the BBB, which may encompass a wide variety of receptors beyond the opioid receptors.

A spoonful of sugar: the application of glycopolymers in therapeutics

“…These are transported into the nucleus and the process of virus replication begins. 13 If initial binding of the virus to the cell 50 can be prevented, subsequent uptake and replication can also be halted. A molecule that could block HA binding efficiently could prove a useful prophylactic during influenza breakouts, such as the recent H1N1 pandemic.…”

“…after injection with radiolabelled histamine; the histamine enters all organs of the body except the brain and spinal column. 49 Glycosylation has 25 recently been shown to be effective at enabling peptides, 50 proteins 51, 52 and nanoparticles 53 to cross the BBB. Currently this area is poorly understood and the mechanism of transport is unknown.…”

“…Finally, polymers may be more directly compared; a single batch of a precursor polymer results in all derivative polymers having the same polydispersity and degree of polymerisation. 45 The precursor polymers of choice were those featuring activated esters, 26,27 such as poly[N-(acryloyloxy) succinimide] (pNAS) or poly[acrylic anhydride] (pAAn), which were reacted with amino-terminated sialosides including 3 and 4. pNAS was treated with a varying number 50 of equivalents of 3 from 0.2-1.2 with respect to the number of succinimide groups; the level of sialoside incorporation was found to correlate directly with the number of sialoside equivalents up the maximum value of 1. After reaction of the sialoside, any remaining succinimide groups were 55 functionalised by addition of an excess of a second amine or ammonia to yield copolymers of various N-substituted acrylamides.…”

“…At approximately 80% MMA the copolymers displayed inhibition in the same order of magnitude as the polysaccharides. Although the level of 50 inhibition is still 2 orders of magnitude worse than that of azidothymdine, a common anti-retroviral, these materials display reduced cytotoxicity in comparison and may have potential in the future.…”

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

“…[29][30][31][32] The integration of these polyhydroxylated, biologically compatible units can serve to alter water solubility and are useful in conjunction with lipidation as a method of customizing the physicochemical properties of a compound to optimize its bioavailability. The synthetic lipo-and glycol-endo-1 analogues assessed in this study are detailed in Figure 1.…”