Glycopeptide-Membrane Interactions:  Glycosyl Enkephalin Analogues Adopt Turn Conformations by NMR and CD in Amphipathic Media

Palian, Michael M.; Boguslavsky, V.; O’Brien, David F.; Polt, Robin

doi:10.1021/ja0268635

Cited by 54 publications

(62 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BBB penetration studies of glycopeptides have indicated up to a 3-fold increase in the rate of brain delivery of these compounds compared with the unglycosylated parent peptides (Bilsky et al, 2000;Egleton et al, 2000Egleton et al, , 2001. Recent studies with glycopeptides in artificial membrane systems indicate that the amphipathicity of the glycopeptides may be an important factor in BBB penetration (Palian et al, 2003). In addition, there is evidence that suggests that the type of glycosylation can alter tissue distribution patterns (Susaki et al, 1999;Suzuki et al, 1999a,b), BBB penetration unpublished results), and peptide/receptor interactions (Gysin and Schwyzer, 1983;Sargent et al, 1988;Palian and Polt, 2001).…”

mentioning

confidence: 99%

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Development of opioid peptides as therapeutic agents has historically been limited due to pharmacokinetic issues including stability and blood-brain barrier (BBB) permeability. Glycosylation of opioid peptides can increase peptide serum stability and BBB penetration. To further define the requirements for optimizing in vivo antinociceptive potency following intravenous administration, we synthesized a series of enkephalin-based glycopeptides using solid phase 9-fluorenylmethyloxy carbamate methods. The compounds differed in the sixth and subsequent amino acid residues (Ser or Thr) and in the attached carbohydrate moiety. In vitro binding and functional smooth muscle bioassays indicated that the addition of mono-or disaccharides did not significantly affect the opioid receptor affinity or agonist activity of the glycopeptides compared with their unglycosylated parent peptides. All of the glycopeptides tested produced potent antinociceptive effects in male ICR mice following intracerebroventricular injection in the 55°C tail-flick test. The calculated A 50 values for the Ser/Thr and monosaccharide combinations were all very similar with values ranging from 0.02 to 0.09 nmol. Selected compounds were administered to mice intravenously and tested for antinociception to indirectly assess serum stability and BBB penetration. All compounds tested produced full antinociceptive effects with calculated A 50 values ranging from 2.2 to 46.4 mol/kg with the disaccharides having potencies that equaled or exceeded that of morphine on a micromoles per kilogram basis. Substitution of a trisaccharide or bis-and tris-monosaccharides resulted in a decrease in antinociceptive potency. These results provide additional support for the utility of glycosylation to increase central nervous system bioavailability of small peptides and compliment our ongoing stability and blood-brain barrier penetration studies.

show abstract

mentioning

confidence: 99%

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…143 Perhaps, we can explain this by Schwyzer's membrane compartment theory, which suggests that the MOR binding site resides in a more hydrophilic environment than the binding site for the DOR. 13 Nevertheless, another point should be highlighted here is that the position of the carbohydrate moiety, type of linkage used, and the kind of sugar moiety introduced are of major consequence to bioactivities of these compounds.…”

Section: B Glycosylationmentioning

confidence: 99%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

View full text Add to dashboard Cite

The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

show abstract

“…126 That is, the amphipathic glycopeptides possess 2 confl icting solubility states: one state that is completely water soluble, and another at water-membrane phase boundaries. However, simply producing highly amphipathic sequences is not enough to promote systemic delivery and penetration of the BBB.…”

Section: E81mentioning

confidence: 99%

CNS Drug Delivery: Opioid Peptides and the Blood-Brain Barrier

Witt¹,

Davis²

2008

Drug Addiction

View full text Add to dashboard Cite

A BSTRACTPeptides are key regulators in cellular and intercellular physiological responses and possess enormous promise for the treatment of pathological conditions. Opioid peptide activity within the central nervous system (CNS) is of particular interest for the treatment of pain owing to the elevated potency of peptides and the centrally mediated actions of pain processes. Despite this potential, peptides have seen limited use as clinically viable drugs for the treatment of pain. Reasons for the limited use are primarily based in the physiochemical and biochemical nature of peptides. Numerous approaches have been devised in an attempt to improve peptide drug delivery to the brain, with variable results. This review describes different approaches to peptide design/modifi cation and provides examples of the value of these strategies to CNS delivery of peptide drugs. The various modes of modifi cation of therapeutic peptides may be amalgamated, creating more effi cacious " hybrid " peptides, with synergistic delivery to the CNS. The ongoing development of these strategies provides promise that peptide drugs may be useful for the treatment of pain and other neurologically-based disease states in the future.

show abstract

Glycopeptide-Membrane Interactions: Glycosyl Enkephalin Analogues Adopt Turn Conformations by NMR and CD in Amphipathic Media

Cited by 54 publications

References 83 publications

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

CNS Drug Delivery: Opioid Peptides and the Blood-Brain Barrier

Contact Info

Product

Resources

About