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

Beier, Laura-Sophie; Rossa, Jan; Woodhouse, Stephen D.; Bergmann, Sophia; Kramer, Holger; Protze, Jonas; Eichner, Miriam; Piontek, Anna; Vidal-y-Sy, Sabine; Brandner, Johanna M.; Krause, Gerd; Zitzmann, Nicole; Piontek, Jörg

doi:10.3390/ijms20194774

Cited by 9 publications

(37 citation statements)

References 70 publications

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“…The C-terminal part of Clostridium perfringens enterotoxin (cCPE) removes claudin-3, -4, -6 and -9 from TJs and was shown to be effective in impairing TJ ion [ 80 ] and molecular tracer [ 67 , 80 ] barriers in reconstructed human epidermis. In addition, it weakened also the SC barrier [ 67 ].…”

Section: Which Skin Barriers Have To Be Overcome?mentioning

confidence: 99%

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

et al. 2020

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Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo.

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Section: Which Skin Barriers Have To Be Overcome?mentioning

confidence: 99%

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

et al. 2020

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“…In addition to BBB applications, the use of cCpE for the intentional opening of tight junction barriers is also being explored in the small intestine and epidermis, where cCpE was found to enhance the transmucosal absorption of dextran and opened the epidermal barrier in reconstructed human epidermis [ 91 , 116 ]. Takahashi et al has screened a cCpE mutant library and isolated a broad claudin-binding mutant called m19, which contains the following mutations: Ser304Ala, Ser305Pro, Ser307Arg, Asn309His, and Ser313His [ 117 ].…”

Section: Applications Of Cpe For Therapeutic Usementioning

confidence: 99%

Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology

Ogbu

Roy

Vecchio

2022

Cells

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Claudins are a family of integral membrane proteins that enable epithelial cell/cell interactions by localizing to and driving the formation of tight junctions. Via claudin self-assembly within the membranes of adjoining cells, their extracellular domains interact, forming barriers to the paracellular transport of small molecules and ions. The bacterium Clostridium perfringens causes prevalent gastrointestinal disorders in mammals by employing an enterotoxin (CpE) that targets claudins. CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling means—the mechanism(s) remain unclear. CpE ultimately destroys claudin-expressing cells through the formation of a cytotoxic membrane-penetrating β-barrel pore. Structures obtained by X-ray crystallography of CpE, claudins, and claudins in complex with CpE fragments have provided the structural bases of claudin and CpE functions, revealing potential mechanisms for the CpE-mediated disruption of claudin-made tight junctions. This review highlights current progress in this space—what has been discovered and what remains unknown—toward efforts to elucidate the molecular mechanism of CpE disruption of tight junction barriers. It further underscores the key insights obtained through structure that are being applied to develop CpE-based therapeutics that combat claudin-overexpressing cancers or modulate tight junction barriers.

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“…Additionally, SC is also found in the infundibulum, forming a double barrier in this region [ 53 ]. The dermal glands generally form TJ barriers, as well, but uptake via glands is not preferred due to their nature of inside-out secretion [ 54 ].…”

Section: Physiological Barriers Hindering Skin Penetration Of Biomacr...mentioning

confidence: 99%

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules

et al. 2022

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Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations.

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

Cited by 9 publications

References 70 publications

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules

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