Novel Lipoamino Acid- and Liposaccharide-Based System for Peptide Delivery:  Application for Oral Administration of Tumor-Selective Somatostatin Analogues

Tóth, István; Malkinson, John P.; Flinn, Nicholas; Drouillat, Bruno; Horváth, Anikó; Érchegyi, Judit; Idei, Miklós; Venetianer, Aniko; Artursson, Per; Lazorova, Lucia; Szende, B.; Kéri, Gÿorgý

doi:10.1021/jm9910167

Cited by 42 publications

(36 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Shorter peptides (6-30 amino acids) corresponding to different sections of the extracellular loops of human occludin were also synthesized. Lipophilic amino acids composed of a linear ␣-side chain of six (hexyl) and twelve (dodecyl) hydrocarbons (Toth et al, 1999), denoted C 8 -and C 14 -, respectively, were added to the N terminus of OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] , resulting in C 8 -OP 90-103 and C 14 -OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] . A schematic illustration of the OPs is given in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Peptide synthesis was accomplished by a stepwise solid-phase procedure on 4-methylbenzhydrylamine-functionalized copoly (styrene-1% divinylbenzene) resin on a 0.25 to 0.75 mmol scale (Toth et al, 1999). The crude peptides were purified by reverse-phase high-performance liquid chromatography (HPLC) on a TSK-GEL C 18 preparative column (5 m) and lyophilized to a final purity of Ͼ95%.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

A New Principle for Tight Junction Modulation Based on Occludin Peptides

Tavelin

Hashimoto²,

Malkinson³

et al. 2003

Mol Pharmacol

Self Cite

105

View full text Add to dashboard Cite

The aim of this study was to investigate whether peptides from the extracellular loops of the tight junction protein occludin could be used as a new principle for tight junction modulation. Peptides of 4 to 47 amino acids in length and covering the two extracellular loops of the tight junction protein occludin were synthesized, and their effect on the tight junction permeability in Caco-2 cells was investigated using [14 C]mannitol as a paracellular marker. Lipopeptide derivatives of one of the active occludin peptides (OPs), synthesized by adding a lipoamino acid containing 14 carbon atoms (C 14 -) to the N terminus of the peptide, were also investigated. Peptides corresponding to the N terminus of the first extracellular loop of occludin increased the permeability of the tight junctions without causing shortterm toxicity. However, the peptides had an effect only when added to the basolateral side of the cells, which could be partly explained by degradation by apical peptidases and aggregate formation. By contrast, the lipopeptide C 14 -OP 90 -103 , which protects the peptide from degradation and aggregation, displayed a rapid apical effect. The L-and D-diastereomers of C 14 -OP 90 -103 had distinctly different effects. The D-isomer, which releases intact OP 90 -103 from the lipoamino acid, displayed a rapid and transient increase in tight junction permeability. The L-isomer, which releases OP 90 -103 more rapidly, gave a more sustained increase in tight junction permeability. In conclusion, C 14 -OP 90 -103 represents a prototype of a new class of tight junction modulators that act on the extracellular domains of tight junction proteins.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A New Principle for Tight Junction Modulation Based on Occludin Peptides

Tavelin

Hashimoto²,

Malkinson³

et al. 2003

Mol Pharmacol

Self Cite

105

View full text Add to dashboard Cite

show abstract

“…Lipoamino acids are a amino acids with long alkyl side-chains, which can enhance the membrane permeability, intestinal absorption and metabolic stability of peptides and have been investigated extensively in drug delivery (Toth et al, 1999;Toth & Keri, 2003). We have assessed the permeability of the lipoamino acid-conjugated A peptides, examined their structure and assessed their ability to release Ca 2 þ from cardiac and skeletal SR vesicles and from the SR in skinned skeletal muscle fibres.…”

Section: Introductionmentioning

confidence: 99%

Functional implications of modifying RyR‐activating peptides for membrane permeability

Dulhunty

Cengia

Young

et al. 2005

British J Pharmacology

View full text Add to dashboard Cite

1 Our aim was to determine whether lipoamino acid conjugation of peptides that are high-affinity activators of ryanodine receptor (RyR) channels would (a) render the peptides membrane permeable, (b) alter their structure or (a) reduce their activity. The peptides correspond to the A region of the II-III loop of the skeletal dihydropyridine receptor. 2 The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco-2 cell monolayer by up to B20-fold. 3 Nuclear magnetic resonance showed that the a-helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation. 4 The conjugated peptides were more effective in enhancing resting Ca 2 þ release, Ca 2 þ -induced Ca 2 þ release and caffeine-induced Ca 2 þ release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine-induced Ca 2 þ release from mechanically skinned extensor digitorum longus (EDL) fibres. 5 The effect of both conjugated and unconjugated peptides on Ca 2 þ release from skeletal SR was 30-fold greater than their effect on either cardiac Ca 2 þ release or on the Ca 2 þ Mg 2 þ ATPase. 6 A small and very low affinity effect of the peptide in slowing Ca 2 þ uptake by the Ca 2 þ , Mg 2 þ ATPase was exacerbated by lipoamino acid conjugation in both isolated SR and in skinned EDL fibres. 7 The results show that lipoamino acid conjugation of A region peptides increases their membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs.

show abstract

“…A solution of 1 mg/ml of each peptide was prepared in PBS containing 5% DMSO, and 300 μl aliquots were mixed with 300 μl of pre-warmed (37˚C) plasma. At selected time points (5,10,20,30,40, 60, 90 and 120 min), samples (50 μl) were collected and mixed with acetonitrile (75 μl) to precipitate plasma proteins which were removed by centrifugation at 10,000 rpm for 10 minutes. The supernatant was analysed for the amount of peptide remaining by RP-HPLC using a Vydac C18 column (5 µm, 4.6 × 250 mm) and an elution gradient of 0% -100% solvent B over 20 min (Solvent A: 0.1% TFA in water; solvent B: 0.1% TFA in 90% acetonitrile/water) at a flow rate of 1.5 ml/min.…”

Section: Plasma Stability Assaymentioning

confidence: 99%

“…Some of the peptide sequences include D-amino acids for increased stability and to test alternative spatial arrangements. We also present lipidated and glycosylated derivatives of these peptides, as these modifications were shown to enhance stability [11,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Mansfeld¹,

Tóth²

2012

IJOC

View full text Add to dashboard Cite

Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the µ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.

show abstract

Novel Lipoamino Acid- and Liposaccharide-Based System for Peptide Delivery: Application for Oral Administration of Tumor-Selective Somatostatin Analogues

Cited by 42 publications

References 14 publications

A New Principle for Tight Junction Modulation Based on Occludin Peptides

A New Principle for Tight Junction Modulation Based on Occludin Peptides

Functional implications of modifying RyR‐activating peptides for membrane permeability

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Contact Info

Product

Resources

About