ArticlePharmaceutical research1997
Esterase-sensitive cyclic prodrugs of peptides: evaluation of a phenylpropionic acid promoiety in a model hexapeptide.
Article in Pharmaceutical research, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 44 citations in OpenAlex.
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- Pathways and progress in improving drug delivery through the intestinal mucosa and blood-brain barriers.Therapeutic delivery · 2014Review
- Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers.Bioorganic & medicinal chemistry · 2012Article
- Prodrugs for amines.Molecules (Basel, Switzerland) · 2008Review
- Cyclization-activated prodrugs.Molecules (Basel, Switzerland) · 2007Review
- Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir.AAPS PharmSciTech · 2003Article
- Characterization of the efflux transporter(s) responsible for restricting intestinal mucosa permeation of an acyloxyalkoxy-based cyclic prodrug of the opioid peptide DADLE.Pharmaceutical research · 2002Article
- Coumarinic acid-based cyclic prodrugs of opioid peptides that exhibit metabolic stability to peptidases and excellent cellular permeability.Pharmaceutical research · 1999Article
- Phenylpropionic acid-based cyclic prodrugs of opioid peptides that exhibit metabolic stability to peptidases and excellent cellular permeation.Pharmaceutical research · 1999Article
- A comparison of the bioconversion rates and the Caco-2 cell permeation characteristics of coumarin-based cyclic prodrugs and methylester-based linear prodrugs of RGD peptidomimetics.Pharmaceutical research · 1998Article
- The effect of beta-turn structure on the passive diffusion of peptides across Caco-2 cell monolayers.Pharmaceutical research · 1997Article
- Effect of restricted conformational flexibility on the permeation of model hexapeptides across Caco-2 cell monolayers.Pharmaceutical research · 1997Article
- Effect of size and charge on the passive diffusion of peptides across Caco-2 cell monolayers via the paracellular pathway.Pharmaceutical research · 1997Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo evaluate a cyclic phenylpropionic acid prodrug of a model hexapeptide (H-Trp-Ala-Gly-Gly-Asp-Ala-OH) as a novel approach to enhance the membrane permeation of a peptide and stabilize it to metabolism.
methodsConversion to the linear hexapeptide was studied at 37 degrees C in HBSS, pH 7.4, and in various biological milieus having measurable esterase activities. Transport and metabolism characteristics were assessed using the Caco-2 cell culture model.
resultsIn aqueous buffered solution, pH 7.4, the cyclic prodrug degraded quantitatively (t1/2 = 1795 +/- 289 min) to the linear hexapeptide and the lactone. Substantially faster degradation of the cyclic prodrug was observed in 90% human plasma (t1/2 = 508 +/- 24 min), and in homogenates of Caco-2 cells (t1/2 = 940 +/- 13 min), the rat intestinal mucosa (t1/2 = 1286 +/- 32 min), and rat liver (t1/2 = 840 +/- 42 min). Pretreatment of these biological media with paraoxon significantly decreased the degradation rate of the prodrug. When applied to the apical side of Caco-2 cell monolayers, the cyclic prodrug was significantly more stable than the hexapeptide and at least 71-fold more able to permeate (P(app) = 1.21 +/- 0.12 X 10(-7) cm/s) than was the parent peptide (P(app) < or = 0.17 x 10(-8) cm/s). In the presence of 0.1 mM palmitoyl-DL-carnitine, the transport rate of the cyclic prodrug (P(app) = 2.19 X 10(-6) cm/s) was 1250-fold greater than that of the linear hexapeptide.
conclusionsPreparation of a cyclic peptide using a phenylpropionic acid promoiety reduced the lability of the peptide to peptidase metabolism and substantially increased its permeation through biological membranes. In various biological media the parent peptide was released from the prodrug by an apparent esterase-catalyzed reaction, sensitive to paraoxon inhibition.
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