Endosomal disentanglement of a transducible artificial transcription factor targeting endothelin receptor A.

Cell-Penetrating Peptides / metabolism Endosomes / metabolism Receptors, Endothelin / metabolism Transcription Factors / metabolism
ETRA/EDNRA TAT peptide artificial transcription factor cathepsin cell-penetrating peptide endosomal entrapment protein transduction zinc finger

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
02 02 2022
Historique:
received: 07 09 2020
revised: 17 08 2021
accepted: 14 09 2021
pubmed: 22 9 2021
medline: 8 4 2022
entrez: 21 9 2021
Statut: ppublish

Résumé

Cell-penetrating peptides (CPPs) hold great promise for intracellular delivery of therapeutic proteins. However, endosomal entrapment of transduced cargo is a major bottleneck hampering their successful application. While developing a transducible zinc finger protein-based artificial transcription factor targeting the expression of endothelin receptor A, we identified interaction between the CPP and the endosomal membrane or endosomal entanglement as a main culprit for endosomal entrapment. To achieve endosomal disentanglement, we utilized endosome-resident proteases to sever the artificial transcription factor from its CPP upon arrival inside the endosome. Using this approach, we greatly enhanced the correct subcellular localization of the disentangled artificial transcription factor, significantly increasing its biological activity and distribution in vivo. With rational engineering of proteolytic sensitivity, we propose a new design principle for transducible therapeutic proteins, helping CPPs attain their full potential as delivery vectors for therapeutic proteins.

Identifiants

DOI: 10.1016/j.ymthe.2021.09.018 PMID: 34547467 PMC: PMC8821953
pubmed: 34547467
pii: S1525-0016(21)00473-1
doi: 10.1016/j.ymthe.2021.09.018
pmc: PMC8821953
pii:
doi:

Substances chimiques

Cell-Penetrating Peptides 0
Receptors, Endothelin 0
Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

855-867

Informations de copyright

Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests This work was supported by contributions to A.N. from Aliophtha AG, Basel, Switzerland, under a research agreement with the University Hospital Basel. Aliophtha AG applied for patents with Aliophtha AG holding intellectual property rights.

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Auteurs

Claudia C Bippes (CC)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Corina Kohler (C)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Esther Garcia-Tirado (E)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Reto Burri (R)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Tina Frauenknecht (T)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Marie-Apolline Gerard (MA)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Marie Salat (M)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Roy Allenspach (R)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Cavit Agca (C)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Zongsong Wu (Z)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland.

Andrea Trost (A)

Department of Ophthalmology, Research Program for Ophthalmology and Glaucoma Research, Paracelsus University, 5020 Salzburg, Austria.

Barbara Bogner (B)

Department of Ophthalmology, Research Program for Ophthalmology and Glaucoma Research, Paracelsus University, 5020 Salzburg, Austria.

Peter Meyer (P)

Department of Ophthalmology, University Basel, 4031 Basel, Switzerland.

Hendrik P N Scholl (HPN)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University Basel, 4031 Basel, Switzerland; Institute of Molecular and Clinical Ophthalmology, 4031 Basel, Switzerland.

Herbert Reitsamer (H)

Department of Ophthalmology, Research Program for Ophthalmology and Glaucoma Research, Paracelsus University, 5020 Salzburg, Austria.

Josef Flammer (J)

Department of Ophthalmology, University Basel, 4031 Basel, Switzerland.

Albert Neutzner (A)

Department of Biomedicine, University Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University Basel, 4031 Basel, Switzerland. Electronic address: albert.neutzner@unibas.ch.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Peptides de pénétration cellulaire › Endosomal disentanglement of a transducible...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Vésicules de transport › Endosomes › Endosomal disentanglement of a transducible...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur endothéline › Endosomal disentanglement of a transducible...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Endosomal disentanglement of a transducible...