Lipophilic derivatives of leu-enkephalinamide: In vitro permeability, stability and in vivo nasal delivery

Cros, Cécile; Tóth, István; Blanchfield, Joanne T.

doi:10.1016/j.bmc.2010.12.042

Cited by 19 publications

(15 citation statements)

References 47 publications

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“…22, 23 Modifications to the C- and N-terminus are relatively simple to accomplish and provide protection against amino- and carboxy-peptidases, but not endopeptidases. 24 Terminal modifications can be used in combination with non-native residues, including N-methylated and D-amino acids, to impart additional stability to peptide bonds. 16, 25, 26 These non-native residues are readily available commercially and are simply incorporated into peptides utilizing standard solid phase peptide synthesis.…”

Section: Introductionmentioning

confidence: 99%

Development of a Peptidase-Resistant Substrate for Single-Cell Measurement of Protein Kinase B Activation

et al. 2012

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An iterative design strategy using three criteria was utilized to develop a peptidase-resistant substrate peptide for protein kinase B. Libraries of peptides possessing non-native amino acids were screened for time to 50% phosphorylation, degradation half-life within a lysate, and appearance of a dominant fragment. The lead peptide possessed a half-life of 92 ± 7 and 16 ± 2 min in HeLa and LNCaP cytosolic lysates, respectively, representing a 4.6- and 2.7-fold lifetime improvement over that of the starting peptide. The redesigned peptide possessed a 4.5-fold improvement in phosphorylation efficiency compared to the starting peptide. The same peptide fragments were formed when the lead peptide was incubated in a lysate or loaded into single cells although the fragments formed in significantly different ratios suggesting that distinct peptidases metabolized the peptide in the two preparations. The rate of peptide degradation and phosphorylation was on average 0.1 ± 0.2 zmol pg−1 s−1 and 0.04 ± 0.08 zmol pg−1 s−1, respectively, for single LNCaP cells loaded with 4 ± 8 μM of peptide. Peptidase-resistant kinase substrates should find wide-spread utility in both lysate-based and single-cell assays of kinase activity.

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Section: Introductionmentioning

confidence: 99%

Development of a Peptidase-Resistant Substrate for Single-Cell Measurement of Protein Kinase B Activation

et al. 2012

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“…Given that the absorption rate for the majority of drug substances is rapid, the degree of absorption relies on physiological factors like the nasal secretion rate, ciliary movement and metabolism (Table 7; Costantino et al, 2007;Karasulu et al, 2008;Kim et al, 2009;Cros et al, 2011;Wang et al, 2012a,b). The nasal secretion and ciliary movement can collectively termed as mucociliary clearance and fluctuate according to health conditions of individual.…”

Section: Challenges Related To Physiological and Pathological Aspectsmentioning

confidence: 99%

Nasal-nanotechnology: revolution for efficient therapeutics delivery

2014

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Context: In recent years, nanotechnology-based delivery systems have gained interest to overcome the problems of restricted absorption of therapeutic agents from the nasal cavity, depending upon the physicochemical properties of the drug and physiological properties of the human nose. Objective: The well-tolerated and non-invasive nasal drug delivery when combined with the nanotechnology-based novel formulations and carriers, opens the way for the effective systemic and brain targeting delivery of various therapeutic agents. To accomplish competent drug delivery, it is imperative to recognize the interactions among the nanomaterials and the nasal biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signaling involved in patho-biology of the disease under consideration. Methods: Quite a few systems have been successfully formulated using nanomaterials for intranasal (IN) delivery. Carbon nanotubes (CNTs), chitosan, polylactic-co-glycolic acid (PLGA) and PLGA-based nanosystems have also been studied in vitro and in vivo for the delivery of several therapeutic agents which shown promising concentrations in the brain after nasal administration. Results and conclusion: The use of nanomaterials including peptide-based nanotubes and nanogels (NGs) for vaccine delivery via nasal route is a new approach to control the disease progression. In this review, the recent developments in nanotechnology utilized for nasal drug delivery have been discussed.

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“…The incorporation of lipids and sugars as conformational constraints (Hruby et al, 1990; Kawai et al, 1990; Hruby and Balse, 2000) significantly improved the pharmacological properties of various peptides (Polt et al, 1994; Egleton et al, 2000; Falconer and Toth, 2007; Cros et al, 2011). …”

Section: Strategies To Improve Bioavailabilitymentioning

confidence: 99%

Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain

Varamini

Tóth

2013

Front. Pharmacol.

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Endomorphins are endogenous opioid peptides that cause potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, endomorphins are poorly suited to clinical applications because of low membrane permeability and a susceptibility to enzymatic degradation. Glycosylation and lipidation have proven to be two of the most robust approaches for the generation of new therapeutic endomorphin derivatives. Conjugation with lipoamino acids (LAA) confers an amphipathic character to the peptide, which improved interaction between the peptide and the lipid bilayer of the cell membranes, increasing permeability. Glycosylation can also improve peptide stability and blood brain barrier (BBB) transport. It is believed that an endocytotic mechanism (transcytosis) is responsible for the systemic delivery of water-soluble glycopeptides. This review discusses the application of glycosylation and lipidation strategies to improve the drug-like properties of endomorphins. Pharmacologically active endomorphin analogs with less adverse effects are also discussed.

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Lipophilic derivatives of leu-enkephalinamide: In vitro permeability, stability and in vivo nasal delivery

Cited by 19 publications

References 47 publications

Development of a Peptidase-Resistant Substrate for Single-Cell Measurement of Protein Kinase B Activation

Development of a Peptidase-Resistant Substrate for Single-Cell Measurement of Protein Kinase B Activation

Nasal-nanotechnology: revolution for efficient therapeutics delivery

Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain

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