Synthesis and in vitro evaluation of lipoamino acid and carbohydrate-modified enkephalins as potential antinociceptive agents

Kellam, Barrie; Drouillat, Bruno; Dékány, Gyula; Starr, Mike S.; Tóth, István

doi:10.1016/s0378-5173(97)00328-1

Cited by 42 publications

(30 citation statements)

References 14 publications

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“…33,34 Lipo-, glyco-, and glycolipidconjugates of Leu-enkephalin (an endogenous opioid that regulates pain and nociception) have been assessed for their ability to improve peptide stability (resistance to intra and extracellular peptidases), as well as their permeability. 36 The conjugation of a single lipoamino acid to the C-terminus of Leu-enkephalin was shown to maintain (slight increase) the biological activity of the parent drug. In comparison, C-terminal conjugation of a glucuronic acid to Leu-enkephalin increased its biological activity by 40-fold, and induced a high selectivity toward the d-opioid receptor.…”

Section: Peptide Deliverymentioning

confidence: 99%

“…In comparison, C-terminal conjugation of a glucuronic acid to Leu-enkephalin increased its biological activity by 40-fold, and induced a high selectivity toward the d-opioid receptor. 36 Similar modifications (lipidation, glycosylation) have been examined for endomorphin 1 (Tyr-Pro-Trp-Phe-NH 2 ), an endogenous peptide that has high affinity and selectivity for m-opioid receptors, and mediates acute and neuropathic pain. Endomorphin 1 was modified through the attachment of lipoamino acids and/or sugars and substitution of tyrosine by 2 0 ,6 0 -dimethyltyrosine.…”

Section: Peptide Deliverymentioning

confidence: 99%

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Modern lipid‐, carbohydrate‐, and peptide‐based delivery systems for peptide, vaccine, and gene products

Simerská

Moyle

Tóth

2011

Medicinal Research Reviews

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Research related to peptide, vaccine, and gene delivery has grown exponentially over the last decade. In this review, we discuss the development of delivery systems for peptides, gene and vaccine products. Special focus is given to different lipidation and glycosylation strategies to improve the metabolic stability and membrane permeability of therapeutics, and their targeting to specific sites. The synthetic methods for preparation of the systems are also described.

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Section: Peptide Deliverymentioning

confidence: 99%

Section: Peptide Deliverymentioning

confidence: 99%

Modern lipid‐, carbohydrate‐, and peptide‐based delivery systems for peptide, vaccine, and gene products

Simerská

Moyle

Tóth

2011

Medicinal Research Reviews

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“…insulin) has been shown to potentially improve both hydrolytic stability and membrane permeation, thus facilitating the passage of compounds across the intestinal epithelium as well as the blood brain barrier. 17 Here, we examined the influence of both lipid conjugation of a C 12 a-lipoamino acid to either the N-or C-terminus of IM862, and glycoyl coupling of glucose-based moieties. A series of Glu-Trp conjugates was prepared using stepwise solidphase peptide synthesis methods and characterized upon purification.…”

Section: Introductionmentioning

confidence: 99%

Oral absorption enhancement of dipeptide L‐Glu‐L‐Trp‐OH by lipid and glycosyl conjugation

Bergeon¹,

Chan²,

Charles³

et al. 2008

Biopolymers

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In recent years, the conjugation of sugar moieties and lipoamino acids has been extensively investigated as a mean to enhance the stability towards enzymatic degradation and the permeability across biological membranes of poorly orally available drugs, including peptides. In this prospect, a library of novel derivatives of the dipeptide L-Glu-L-Trp, a naturally occurring thymic immunomodulator with high hydrophilic character and low membrane permeability, was designed and synthesised by conjugating 2-amino-dodecanoic acid (C(12)) and/or 1-amino-beta-D-glucuronic acid (GlcAN), beta-D-glucuronic acid (GlcA) and N-beta-D-glucopyranosylamine succinamic acid (GlsNS) residues to the Glu-Trp scaffold, using an Fmoc solid-phase peptide synthesis strategy on trichlorotrityl resin. A cellobiose derivative was also prepared in solution. The synthesized peptides showed no sign of toxicity to red blood cells at 200 microM (haemolysis assay) and their resistance against enzymatic hydrolysis, assessed in Caco-2 homogenates, was usually significantly increased, particularly for the C-terminal conjugates. Several derivatives also saw their apparent permeability values greatly enhanced and one of the conjugates tested proved to be able to release the initial dipeptide after penetrating Caco-2 monolayers. An initial in vivo experiment was then carried out in male Wistar rats to examine the effect of conjugation on the absorption rate and bioavailability.

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“…1). Such liposaccharide-type conjugates have recently been proposed ] with the aim, e.g., of increasing the stability of peptide drugs administered orally [Toth et al, 1999] or to enhance the biological activity of enkephalin derivatives [Kellam et al, 1998]. …”

Section: Introductionmentioning

confidence: 99%

Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Pignatello

Vicari

Sorrenti

et al. 2001

Drug Development Research

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To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA-MTX conjugates previously described. In vitro biological testing of LAAG-MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454-461, 2001.

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Synthesis and in vitro evaluation of lipoamino acid and carbohydrate-modified enkephalins as potential antinociceptive agents

Cited by 42 publications

References 14 publications

Modern lipid‐, carbohydrate‐, and peptide‐based delivery systems for peptide, vaccine, and gene products

Modern lipid‐, carbohydrate‐, and peptide‐based delivery systems for peptide, vaccine, and gene products

Oral absorption enhancement of dipeptide L‐Glu‐L‐Trp‐OH by lipid and glycosyl conjugation

Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

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