Trans-Mediated, Cis-Inhibited Paradoxal Activity of Clostridium perfringens Enterotoxin (c-CPE) in Modulating Epithelial Permeability
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| Title: | Trans-Mediated, Cis-Inhibited Paradoxal Activity of Clostridium perfringens Enterotoxin (c-CPE) in Modulating Epithelial Permeability |
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| Authors: | Julieta M. Sanchez, Marianna T. P. Favaro, Hèctor López-Laguna, Eloi Parladé, Angela Di Somma, Isolda Casanova, Ugutz Unzueta, Ramón Mangues, Esther Vazquez, Eric Voltà-Durán, Antonio Villaverde |
| Source: | Mol Pharm UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| Publisher Information: | American Chemical Society (ACS), 2025. |
| Publication Year: | 2025 |
| Subject Terms: | Recombinant protein, Cell Membrane Permeability, Clostridium perfringens, Àrees temàtiques de la UPC::Ciències de la salut, Recombinant Fusion Proteins, Epithelial Cells, Article, Permeability, CCPE, Claudin, Tight Junctions, Enterotoxins, cCPE, claudin, drug delivery, nanoparticles, recombinant protein, transactivity, Drug delivery, Transactivity, Claudins, Nanoparticles, Humans, Caco-2 Cells |
| Description: | In the context of transdermal delivery, favoring the drug permeability of epithelia through convenient formulations would open new opportunities for local versus systemic drug delivery, envisaging higher patient comfort and an enhanced therapeutic effect. Ligands of tight junctions are interesting agents that enhance epithelial permeability by relaxing the protein complexes that form them. The C-terminal domain of Clostridium perfringens enterotoxin (c-CPE), which binds claudins, one of the tight junction (TJ) components, has been explored here as a functional domain in modular recombinant proteins, to evaluate its ability to self-promote its paracellular epithelial passage in a Caco-2 cell monolayer model. c-CPE-containing fusion proteins bind cells in the absence of internalization and cytotoxicity and support the passage, in trans, of other fusion proteins devoid of c-CPE. However, c-CPE-carrying proteins fail to cross the epithelia by themselves, probably because their affinity for TJs immobilizes them in the intercellular space. Therefore, while recombinant c-CPE versions have been here confirmed as convenient epithelial-permeabilizing agents, a paradoxical behavior has been observed where this effect is only successful when applied in trans, specifically on entities that lack c-CPE. Then, c-CPE itself inhibits the paracellular mobility of carrier molecules, not being suited as a self-driver (in c-CPE-drug complexes) for drug delivery through epithelia. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.4c01205 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/40067325 https://hdl.handle.net/11588/1004478 https://ddd.uab.cat/record/309270 |
| Rights: | CC BY CC 0 URL: http://creativecommons.org/licenses/by/4.0/This article is licensed under CC-BY 4.0 |
| Accession Number: | edsair.doi.dedup.....8a8b88cafe7c69d6f335e22f2ea2ddab |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | In the context of transdermal delivery, favoring the drug permeability of epithelia through convenient formulations would open new opportunities for local versus systemic drug delivery, envisaging higher patient comfort and an enhanced therapeutic effect. Ligands of tight junctions are interesting agents that enhance epithelial permeability by relaxing the protein complexes that form them. The C-terminal domain of Clostridium perfringens enterotoxin (c-CPE), which binds claudins, one of the tight junction (TJ) components, has been explored here as a functional domain in modular recombinant proteins, to evaluate its ability to self-promote its paracellular epithelial passage in a Caco-2 cell monolayer model. c-CPE-containing fusion proteins bind cells in the absence of internalization and cytotoxicity and support the passage, in trans, of other fusion proteins devoid of c-CPE. However, c-CPE-carrying proteins fail to cross the epithelia by themselves, probably because their affinity for TJs immobilizes them in the intercellular space. Therefore, while recombinant c-CPE versions have been here confirmed as convenient epithelial-permeabilizing agents, a paradoxical behavior has been observed where this effect is only successful when applied in trans, specifically on entities that lack c-CPE. Then, c-CPE itself inhibits the paracellular mobility of carrier molecules, not being suited as a self-driver (in c-CPE-drug complexes) for drug delivery through epithelia. |
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| ISSN: | 15438392 15438384 |
| DOI: | 10.1021/acs.molpharmaceut.4c01205 |