Use of Modified Clostridium perfringens Enterotoxin Fragments for Claudin Targeting in Liver and Skin Cells
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Use of Modified Clostridium perfringens Enterotoxin Fragments for Claudin Targeting in Liver and Skin Cells. / Beier, Laura-Sophie; Rossa, Jan; Woodhouse, Stephen; Bergmann, Sophia; Kramer, Holger B; Protze, Jonas; Eichner, Miriam; Piontek, Anna; Vidal-Y-Sy, Sabine; Brandner, Johanna M; Krause, Gerd; Zitzmann, Nicole; Piontek, Jörg.
in: INT J MOL SCI, Jahrgang 20, Nr. 19, 26.09.2019.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Use of Modified Clostridium perfringens Enterotoxin Fragments for Claudin Targeting in Liver and Skin Cells
AU - Beier, Laura-Sophie
AU - Rossa, Jan
AU - Woodhouse, Stephen
AU - Bergmann, Sophia
AU - Kramer, Holger B
AU - Protze, Jonas
AU - Eichner, Miriam
AU - Piontek, Anna
AU - Vidal-Y-Sy, Sabine
AU - Brandner, Johanna M
AU - Krause, Gerd
AU - Zitzmann, Nicole
AU - Piontek, Jörg
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
KW - Amino Acid Substitution
KW - Cell Line, Tumor
KW - Claudins/chemistry
KW - Enterotoxins/chemistry
KW - Epidermis/metabolism
KW - Hepacivirus/drug effects
KW - Hepatitis C/metabolism
KW - Hepatocytes/metabolism
KW - Humans
KW - Models, Molecular
KW - Molecular Conformation
KW - Protein Binding
KW - Skin/cytology
KW - Virus Internalization/drug effects
KW - Virus Replication
U2 - 10.3390/ijms20194774
DO - 10.3390/ijms20194774
M3 - SCORING: Journal article
C2 - 31561440
VL - 20
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 19
ER -