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Int J Mol Sci. 2019 Sep 26;20(19). pii: E4774. doi: 10.3390/ijms20194774.

Use of Modified Clostridium perfringens Enterotoxin Fragments for Claudin Targeting in Liver and Skin Cells.

Author information

1
Charité-Universitätsmedizin Berlin, Institute of Clinical Physiology, Hindenburgdamm 30, 12203 Berlin, Germany. Laura-Sophie.Beier@charite.de.
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. JanRossa@gmx.de.
3
Oxford Glycobiology Institute, Department of Biochemistry, South Parks Road, University of Oxford, Oxford OX1 3QU, UK. Stephen.woodhouse@cardiov.ox.ac.uk.
4
Department of Dermatology and Venerology, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany. s.bergmann@t-online.de.
5
Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX3 7DQ, UK. h.kramer@lms.mrc.ac.uk.
6
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. Protze@fmp-berlin.de.
7
Charité-Universitätsmedizin Berlin, Institute of Clinical Physiology, Hindenburgdamm 30, 12203 Berlin, Germany. miriam.eichner@googlemail.com.
8
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. dr.anna.piontek.ext@bayer.com.
9
Department of Dermatology and Venerology, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany. s.vidal-y-sy@uke.de.
10
Department of Dermatology and Venerology, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany. brandner@uke.de.
11
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany. GKrause@fmp-berlin.de.
12
Oxford Glycobiology Institute, Department of Biochemistry, South Parks Road, University of Oxford, Oxford OX1 3QU, UK. nicole.zitzmann@bioch.ox.ac.uk.
13
Charité-Universitätsmedizin Berlin, Institute of Clinical Physiology, Hindenburgdamm 30, 12203 Berlin, Germany. joerg.piontek@charité.de.

Abstract

Claudins regulate paracellular permeability in different tissues. The claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) is a known modulator of a claudin subset. However, it does not efficiently bind to claudin-1 (Cldn1). Cldn1 is a pharmacological target since it is (i) an essential co-receptor for hepatitis C virus (HCV) infections and (ii) a key element of the epidermal barrier limiting drug delivery. In this study, we investigated the potential of a Cldn1-binding cCPE mutant (i) to inhibit HCV entry into hepatocytes and (ii) to open the epidermal barrier. Inhibition of HCV infection by blocking of Cldn1 with cCPE variants was analyzed in the Huh7.5 hepatoma cell line. A model of reconstructed human epidermis was used to investigate modulation of the epidermal barrier by cCPE variants. In contrast to cCPEwt, the Cldn1-binding cCPE-S305P/S307R/S313H inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner. In addition, TJ modulation by cCPE variant-mediated targeting of Cldn1 and Cldn4 opened the epidermal barrier in reconstructed human epidermis. cCPE variants are potent claudin modulators. They can be applied for mechanistic in vitro studies and might also be used as biologics for therapeutic claudin targeting including HCV treatment (host-targeting antivirals) and improvement of drug delivery.

KEYWORDS:

Clostridium perfringens enterotoxin; Hepatitis C Virus; claudin targeting; claudin-1; epidermal barrier; reconstructed human epidermis; viral entry

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