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.
Highlights
Claudins, tetraspan transmembrane proteins, are key structural and sealing components of tight junctions (TJ)
TJ modulation by claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) variant-mediated targeting of Cldn1 and Cldn4 opened the epidermal barrier in reconstructed human epidermis. cCPE variants are potent claudin modulators
This enabled targeting of Cldn1-9 with the broad specificity binder cCPE-S305P/S307R/S313H [5,6], preferential binding to Cldn4 with cCPE-L254A/S256A/I258A/D284A [7] or preferential binding to Cldn5 with cCPE-Y306W/S313H and cCPE-N218Q/Y306W/S313H [6,8]
Summary
Tetraspan transmembrane proteins, are key structural and sealing components of tight junctions (TJ). Cldn is an essential co-factor in hepatitis C virus (HCV) entry into hepatocytes [13]. The multi-claudin binder cCPE-SSS might be a suitable agent to inhibit HCV receptor formation by binding Cldn and thereby blocking HCV entry into hepatocytes. It was suggested that Cldn plays a dual role in HCV entry [25]: (i) formation of a HCV co-receptor complex with CD81 [26] and (ii) direct interaction with the virus envelope E1E2 proteins [27]. As an alternative HCV treatment, in this study, we investigated the potential of claudin-binding cCPE variants to block HCV infection. Targeting of extra-junctional Cldn in hepatocytes, which serves as a co-receptor for HCV infection, by cCPE-SSS efficiently inhibited HCV infection. We showed that cCPE variants are suitable for directed claudin targeting
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