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Fujita, Takuya; Kawahara, Iichiro; Quan, Ying‐Shu; Hattori, Koji; Takenaka, Kayo; Muranishi, Shozo; Yamamoto, Akira

doi:10.1023/a:1011997404306

Cited by 30 publications

(4 citation statements)

References 13 publications

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“…Although there are many reports on the oral administration of lipidized peptides, including insulin [66], tetragastrin [67], DADLE [68], calcitonin [62], and enkephalin [58], none of them has been further developed into an advanced development stage. One of the limitations of using lipidized peptides for oral delivery is the lack of a systematic study of the mechanism of enhanced oral absorption.…”

Section: Acylation Of Therapeutic Molecules With Fatty Acidsmentioning

confidence: 99%

“…One of the limitations of using lipidized peptides for oral delivery is the lack of a systematic study of the mechanism of enhanced oral absorption. In addition, there are many factors, such as the linker used in lipid-conjugation, the formulations for oral administration, and the presence of other excipients that can influence the oral bioavailability of a lipidized peptide [67–70]. Nevertheless, all of the studies have shown that, compared to unmodified peptide, the lipidized peptidyl drugs exhibited improvements in the pharmacological activity as well as an increased mucosal permeability, plasma concentration, and area under the curve (AUC).…”

Section: Acylation Of Therapeutic Molecules With Fatty Acidsmentioning

confidence: 99%

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Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

Hackett

Zaro

Shen

et al. 2013

Advanced Drug Delivery Reviews

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Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides have exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes.

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Section: Acylation Of Therapeutic Molecules With Fatty Acidsmentioning

confidence: 99%

Section: Acylation Of Therapeutic Molecules With Fatty Acidsmentioning

confidence: 99%

Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

Hackett

Zaro

Shen

et al. 2013

Advanced Drug Delivery Reviews

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“…Both acetylation and/or caproylation of CCK4-NH 2 resulted in increased peptide stability, permeability and intestinal absorption [29]–[32]. In addition to CCK, lipidation has been utilized to modify a wide variety of peptide ligands [33].…”

Section: Discussionmentioning

confidence: 99%

A Two-Step Strategy to Enhance Activity of Low Potency Peptides

et al. 2014

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Novel strategies are needed to expedite the generation and optimization of peptide probes targeting G protein-coupled receptors (GPCRs). We have previously shown that membrane tethered ligands (MTLs), recombinant proteins comprised of a membrane anchor, an extracellular linker, and a peptide ligand can be used to identify targeted receptor modulators. Although MTLs provide a useful tool to identify and/or modify functionally active peptides, a major limitation of this strategy is the reliance on recombinant protein expression. We now report the generation and pharmacological characterization of prototype peptide-linker-lipid conjugates, synthetic membrane anchored ligands (SMALs), which are designed as mimics of corresponding MTLs. In this study, we systematically compare the activity of selected peptides as MTLs versus SMALs. As prototypes, we focused on the precursor proteins of mature Substance P (SubP) and Cholecystokinin 4 (CCK4), specifically non-amidated SubP (SubP-COOH) and glycine extended CCK4 (CCK4-Gly-COOH). As low affinity soluble peptides these ligands each presented a challenging test case for assessment of MTL/SMAL technology. For each ligand, MTLs and corresponding SMALs showed agonist activity and comparable subtype selectivity. In addition, our results illustrate that membrane anchoring increases ligand potency. Furthermore, both MTL and SMAL induced signaling can be blocked by specific non-peptide antagonists suggesting that the anchored constructs may be orthosteric agonists. In conclusion, MTLs offer a streamlined approach for identifying low activity peptides which can be readily converted to higher potency SMALs. The ability to recapitulate MTL activity with SMALs extends the utility of anchored peptides as probes of GPCR function.

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“…28,29) The quantity of compounds permeated to the basal side was evaluated as fluorescence intensity, derived from both FE-heptaarginine and produced FE 1, in the basal medium. Paap values were calculated based on this basal fluorescence.…”

Section: Conversion Of Compounds 4a-g To Fementioning

confidence: 99%

Oligoarginine-Based Prodrugs with Self-Cleavable Spacers for Caco-2 Cell Permeation

Takayama

Suehisa

Fujita

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Many kinds of cell penetrating peptides (CPPs) [1][2][3][4][5][6][7][8][9] including oligoarginine peptides have been widely used as attractive tools for intracellular delivery of various substances with low membrane permeability. 2,[10][11][12][13][14][15][16][17][18] Highly cationic clusters composed of constitutive basic guanidino groups in oligoarginine peptides are known to interact with negativecharged proteoglycans on the surface of cells and internalize by macropinocytosis. [19][20][21][22] However, the precise internalization mechanism of these CPPs has yet been elaborated.Only recently drug conjugates with oligoarginine peptides have been expected to increase the penetration of low permeable drugs through the intestinal epithelial cell layer into blood. [23][24][25] In our previous study, we proposed a new selfcleavable spacer in the oligoarginine-based cargo-transporter (OACT) system toward effective intestinal absorption. 25) This spacer was designed to release the parent drug from a hydrophilic oligoarginine moiety inside the cells, in order to transport the parent drug into blood through the hydrophobic basal-side cell membrane, after the conjugate had penetrated from the apical-side of cells with the assistance of oligoarginine (Fig. 1). Fluorescein isothiocyanate (FITC)-ethanolamine (FE 1) and H-GABA-D-Arg 7 -NH 2 were chosen as a drug-model with low intestinal permeability and an oligoarginine-based CPP, respectively. Using on Fmocbased solid phase peptide synthesis (SPPS), three kinds of oligoarginine-drug model conjugates 4a-c, which were connected by this chemical-triggered self-cleavable spacers, were synthesized, and their conversion times to parent FE 1 via an intramolecular succinimide formation was investigated.25) The conversion times of these compounds (4a-c) were different with t 1/2 values ranging from 9 to 100 min. Moreover, the conversion time was well controlled by the neighboring-group participation of an adjacent amino acid side-chain structure to the succinyl moiety within the spacer In the development of oligoarginine-based prodrugs with self-cleavable spacers for intestinal absorption, we previously reported a series of spacers with variable half-lives of parent compound release based on a neighboring group participation mechanism from an amino acid side-chain structure next to the succinyl moiety. In the present study, to diversify the half-life of the spacer, we first synthesized several additional fluorescein isothiocyanate ethanolamine (FE)-heptaarginine conjugates (4d-g) and evaluated their conversion time. To investigate the overall cellular uptake of FE-heptaarginine conjugates, the cellular uptakes of FE-heptaarginines 4a and 4b possessing the longest and shortest half-lives, respectively, were evaluated using HeLa cells by confocal microscopy and flow cytometry. Conjugate 4a with a longer half-life was more efficiently taken up by the cells than conjugate 4b. However, in term of the transport rate of parent FE 1 in in vitro Caco-2 cell permeation assay, conjugate 4b ...

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Abstract: We demonstrated that acylation of TG made it resistant to intestinal proteases and caused it to enhance absorption of drugs, including itself, across Caco-2 monolayers. Further, bacitracin acted as both a protease inhibitor and an absorption enhancer.

Cited by 30 publications

References 13 publications

Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

A Two-Step Strategy to Enhance Activity of Low Potency Peptides

Oligoarginine-Based Prodrugs with Self-Cleavable Spacers for Caco-2 Cell Permeation

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