Biousian glycopeptides penetrate the blood–brain barrier

Egleton, Richard D.; Bilsky, Edward J.; Tollin, Gordon; Dhanasekaran, M.; Lowery, John J.; Alves, Isabel D.; Davis, Peg; Porreca, Frank; Yamamura, Henry I.; Yeomans, Larisa; Keyari, Charles M.; Polt, Robin

doi:10.1016/j.tetasy.2004.11.038

Cited by 41 publications

(46 citation statements)

References 29 publications

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“…Indeed, MMP2200 and morphine were roughly equipotent on a milligram/kilogram basis after systemic administration in this assay in mice (cf. morphine and compound 5 in Egleton et al, 2005). These behavioral findings in mice were consistent with pharmacokinetic studies showing that glycosylated peptides related to MMP2200 crossed the blood-brain barrier and gained access to brain after systemic administration (Egleton et al, 2005).…”

Section: Discussionsupporting

confidence: 84%

“…Results of antagonism studies suggest that the antiallodynic effects of MMP2200 were mediated by peripheral -and ␦-opioid receptors. Although glycosylation of MMP2200 and related peptides has been reported to promote distribution across the blood-brain barrier in rodents after intravenous, intraperitoneal, and subcutaneous administration (Bilsky et al, 2000;Elmagbari et al, 2004;Egleton et al, 2005), intramuscularly and intravenously administered MMP2200 did not produce several effects thought to be mediated by central opioid receptors in the present study in rhesus monkeys. Overall, these results suggest that systemically administered MMP2200 acted as a peripheral /␦-opioid agonist with limited distribution to the central nervous system in rhesus monkeys.…”

Section: Discussioncontrasting

confidence: 75%

“…The differences are also probably not attributable to differential distribution associated with different routes of MMP2200 administration. Studies in mice used intravenous, subcutaneous, and intraperitoneal routes of administration for MMP2200 and related glycopeptides (Bilsky et al, 2000;Elmagbari et al, 2004;Egleton et al, 2005), whereas the present study used intravenous and intramuscular routes. To some extent, the contrast in results from mouse and nonhuman primate studies suggests that there may be species differences in pharmacokinetics or pharmacodynamics of MMP2200.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MMP2200 was ϳ10-fold more potent than the parent compound in producing antinociception in mice after systemic (intravenous) administration (compare compounds 1 and 9 in Elmagbari et al, 2004). These results were interpreted to suggest that glycosylation increased stability and/or penetration of the blood-brain barrier, and subsequent kinetic studies provided evidence to support both possibilities (Egleton et al, 2005). Taken together, these in vitro studies and behavioral studies suggest that MMP2200 may be a promising lead compound in the development of glycosylated /␦-opioid peptides as analgesic drugs.…”

mentioning

confidence: 96%

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Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Carmo

Polt²,

Bilsky³

et al. 2008

J Pharmacol Exp Ther

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H 2 N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-␤-D-lactose)-CONH 2 (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for and ␦ receptors. Glycosylation promoted brain penetration and production of centrally mediated behavioral effects in mice; however, it is unknown whether the magnitude of enhanced brain penetration is sufficient to permit central mediation of drug effects and production of synergistic /␦ antinociceptive interactions after systemic administration in primates. To address this issue, the present study compared the effects of MMP2200 and the -agonist morphine in four behavioral procedures in rhesus monkeys. In an assay of thermal nociception, morphine (1.0 -5.6 mg/kg) produced dose-dependent antinociception, whereas MMP2200 (10 -56 mg/kg) was ineffective. In an assay of capsaicin-induced thermal allodynia, both morphine (0.01-1.0 mg/kg) and MMP2200 (0.032-3.2 mg/kg) produced dose-dependent antiallodynic effects. MMP2200-induced antiallodynia was blocked by the moderately -selective antagonist naltrexone (0.01 mg/kg), the ␦-selective antagonist naltrindole (1.0 mg/kg), and the peripherally selective opioid antagonist quaternary naltrexone (0.32 mg/kg). In an assay of schedulecontrolled behavior, both morphine (0.01-1.0 mg/kg) and MMP2200 (10 -56 mg/kg) decreased response rates. Morphine effects were antagonized by naltrexone (0.001-0.01 mg/kg); however, the effects of MMP2200 were not antagonized by either naltrexone (0.01 mg/kg) or naltrindole (1.0 mg/kg). In an assay of drug self-administration, morphine (0.0032-0.32 mg/kg/injection) produced reinforcing effects, whereas MMP2200 (0.032-0.32 mg/kg/injection) did not. These results suggest that systemically administered MMP2200 acted as a peripheral, /␦-opioid agonist with limited distribution to the central nervous system in rhesus monkeys. These results also suggest the existence of species differences in the pharmacokinetics and brain penetration of glycopeptides.Opioids act at three main types of opioid receptor-the , ␦, and receptors-and most opioid analgesics function primarily as agonists at receptors (Gutstein and Akil, 2005). One strategy to improve the therapeutic usefulness of opioids has been to combine -receptor activation with pharmacological manipulation of other targets to produce a net increase in desirable versus undesirable effects. For example, simultaneous activation of -and ␦-opioid receptors may produce enhanced antinociception with fewer undesirable effects than selective activation of either or ␦ receptors alone in both rodents (Vaught and Takemori, 1979;Heyman et al., 1989;Adams et al., 1993) and nonhuman primates (Dykstra et al., 2002;Stevenson et al., 2003).The simultaneous activation of and ␦ receptors can be achieved either with a mixture of selective and ␦ opioids or with a single compound that has mixed activity at both and ␦ receptors. Endogenous opioid neurotransmitters such as Met-and Leu-enkephalin represent one class of opioid receptor ligands that produce relatively nonselective agonist effe...

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Section: Discussionsupporting

confidence: 84%

Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Carmo

Polt²,

Bilsky³

et al. 2008

J Pharmacol Exp Ther

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“…This work has now led us to explore the influence of glycosylation on the cellular uptake, taking as a starting point our lead (R6/W3) CPP sequence [19][20][21]. Glycosylation of bioactive compounds has been used mainly for increasing either the hydrophilicity, the enzymatic stability of the compound, and/or its delivery into the brain [22][23][24][25]. In the context of CPPs, we have hypothesized that glycosylation may regulate and or affect the internalization of the corresponding glycosylated analogs of (R6/W3) [26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

et al. 2009

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Cell-penetrating peptides (CPPs), which are usually short basic peptides, are able to cross cell membranes and convey bioactive cargoes inside cells. CPPs have been widely used to deliver inside cells peptides, proteins, and oligonucleotides; however, their entry mechanisms still remain controversial. A major problem concerning CPPs remains their lack of selectivity to target a specific type of cell and/or an intracellular component. We have previously shown that myristoylation of one of these CPPs affected the intracellular distribution of the cargo. We report here on the synthesis of glycosylated analogs of the cell-penetrating peptide (R6/W3): Ac-RRWWRRWRR-NH 2 . One, two, or three galactose(s), with or without a spacer, were introduced into the sequence of this nonapeptide via a triazole link, the Huisgen reaction being achieved on a solid support. Four of these glycosylated CPPs were coupled via a disulfide bridge to the proapoptotic KLAK peptide, (KLAKLAKKLAKLAK), which alone does not enter into cells. The effect on cell viability and the uptake efficiency of different glycosylated conjugates were studied on CHO cells and were compared to those of the nonglycosylated conjugates: (R6/W3)S-S-KLAK and penetratinS-S-KLAK. We show that glycosylation significantly increases the cell viability of CHO cells compared to the nonglycosylated conjugates and concomitantly decreases the internalization of the KLAK cargo. These results suggest that glycosylation of CPP may be a key point in targeting specific cells.

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Modification with Organometallic Compounds Improves Crossing of the Blood–Brain Barrier of [Leu⁵]‐Enkephalin Derivatives in an In Vitro Model System

et al. 2009

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Enkephalin peptides are thought to be suitable vectors for the passage of the blood-brain barrier (BBB). Modifications that do not alter the amino acid sequence are often used to improve the permeation through living membrane systems. As a new type of modification we introduce organometallic compounds, in particular ferrocene carboxylic acid. Derivatives of [Leu5]enkephalin were synthesised and labelled with organometallic compounds by using solid-phase synthesis techniques. All new metal-peptide bioconjugates were comprehensively characterised by HPLC, NMR spectroscopy and mass spectrometry and found to be at least 95% pure. For the first time, permeation coefficients in a BBB model for organometal-peptide derivatives were determined in this work. The uptake and localisation of fluorescein-labelled enkephalins was monitored by fluorescence microscopy on three cancer cell lines. Octanol/H2O partition coefficients of the compounds were measured by HPLC. The introduction of the organometallic moiety enhances the uptake into cells and the permeation coefficient of [Leu5]-enkephalin. This could be due to an increase in lipophilicity caused by the organometallic label. The metal-peptide conjugates were found to be nontoxic up to mM concentrations. The low cytotoxicity encourages further experiments that could take advantage of the selectivity of enkephalin derivatives for opioid receptors.

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Biousian glycopeptides penetrate the blood–brain barrier

Cited by 41 publications

References 29 publications

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

Modification with Organometallic Compounds Improves Crossing of the Blood–Brain Barrier of [Leu⁵]‐Enkephalin Derivatives in an In Vitro Model System

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Biousian glycopeptides penetrate the blood–brain barrier

Cited by 41 publications

References 29 publications

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

Modification with Organometallic Compounds Improves Crossing of the Blood–Brain Barrier of [Leu5]‐Enkephalin Derivatives in an In Vitro Model System

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Product

Resources

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Modification with Organometallic Compounds Improves Crossing of the Blood–Brain Barrier of [Leu⁵]‐Enkephalin Derivatives in an In Vitro Model System