ArticlePharmaceutical research1997
Effect of restricted conformational flexibility on the permeation of model hexapeptides across Caco-2 cell monolayers.
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 25 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed.
- A generalizable assay for intracellular accumulation to profile cytosolic drug delivery in mammalian cells.Communications chemistry · 2026Article
- Systematic Determination of the Impact of Structural Edits on Peptide Accumulation into Mycobacteria.ACS chemical biology · 2025Article
- Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- End-to-End Backbone Cyclization Enhances Passive Permeability of bRo5 Oligomeric Depsipeptides with Nonlinear Size Dependence.ACS medicinal chemistry letters · 2025Article
- Peptide Design for Enhanced Anti-Melanogenesis: Optimizing Molecular Weight, Polarity, and Cyclization.Drug design, development and therapy · 2025Review
- Structure of a Cyclic Peptide as an Inhibitor ofPharmaceuticals (Basel, Switzerland) · 2024Article
- Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides.ACS pharmacology & translational science · 2022Article
- Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies.ACS medicinal chemistry letters · 2021Article
- Improvement on Permeability of Cyclic Peptide/Peptidomimetic: BackboneMarine drugs · 2021Review
- Pursuing Orally Bioavailable Hepcidin Analogues via CyclicBiomedicines · 2021Article
- Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints.ACS chemical biology · 2013Review
- Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system.Bioorganic & medicinal chemistry · 2010Article
- Modeling kinetics of subcellular disposition of chemicals.Chemical reviews · 2009Review
- Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides.Biopolymers · 2008Article
- Interplay of secondary structure and charge on the diffusion of a polypeptide through negatively charged aqueous pores.Pharmaceutical research · 2007Article
- A randomly coiled, high-molecular-weight polypeptide exhibits increased paracellular diffusion in vitro and in situ relative to the highly ordered alpha-helix conformer.Pharmaceutical research · 2005Article
- The effect of beta-turn structure on the passive diffusion of peptides across Caco-2 cell monolayers.Pharmaceutical research · 1997Article
- The effect of beta-turn structure on the permeation of peptides across monolayers of bovine brain microvessel endothelial cells.Pharmaceutical research · 1997Article
- Prodrug and analog approaches to improving the intestinal absorption of a cyclic peptide, GPIIb/IIIa receptor antagonist.Pharmaceutical research · 1997Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
Abstract
purposeTo determine how restricted conformational flexibility of hexapeptides influences their cellular permeation characteristics.
methodsLinear (Ac-Trp-Ala-Gly-Gly-X-Ala-NH2; X = Asp, Asn, Lys) and cyclic (cyclo[Trp-Ala-Gly-Gly-X-Ala]; X = Asp, Asn, Lys) hexapeptides were synthesized, and their transport characteristics were assessed using the Caco-2 cell culture model. The lipophilicities of the hexapeptides were determined using an immobilized artificial membrane. Diffusion coefficients used to calculate molecular radii were determined by NMR. Two-dimensional NMR spectroscopy, circular dichroism, and molecular dynamic simulations were used to elucidate the most favorable solution structure of the cyclic Asp-containing peptide.
resultsThe cyclic hexapeptides used in this study were 2-3 times more able to permeate (e.g., Papp = 9.3 +/- 0.3 x 10(-8) cm/sec, X = Asp) the Caco-2 cell monolayer than were their linear analogs (e.g., Papp = 3.2 +/- 0.3 x 10(-8) cm/sec, X = Asp). In contrast to the linear hexapeptides, the flux of the cyclic hexapeptides was independent of charge. The cyclic hexapeptides were shown to be more lipophilic than the linear hexapeptides as determined by their retention times on an immobilized phospholipid column. Determination of molecular radii by two different techniques suggests little or no difference in size between the linear and cyclic hexapeptides. Spectroscopic data indicate that the Asp-containing linear hexapeptide exists in a dynamic equilibrium between random coil and beta-turn structures while the cyclic Asp-containing hexapeptide exists in a well-defined compact amphophilic structure containing two beta-turns.
conclusionsCyclization of the linear hexapeptides increased their lipophilicities. The increased permeation characteristics of the cyclic hexapeptides as compared to their linear analogs appears to be due to an increase in their flux via the transcellular route because of these increased lipophilicities. Structural analyses of the cyclic Asp-containing hexapeptide suggest that its well-defined solution structure and, specifically the existence of two beta-turns, explain its greater lipophilicity.
Indexed as
Identifiers
9090704What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.