Identification and characterization of highly versatile peptide-vectors that bind non-competitively to the low-density lipoprotein receptor for in vivo targeting and delivery of small molecules and protein cargos
| Autor: | David, Marion, Lecorché, Pascaline, Masse, Maxime, Faucon, Aude, Abouzid, Karima, Gaudin, Nicolas, Varini, Karine, Gassiot, Fanny, Ferracci, Geraldine, Jacquot, Guillaume, Vlieghe, Patrick, Khrestchatisky, Michel |
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| Přispěvatelé: | Vect-Horus, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2017 |
| Předmět: |
Male
Cell Membranes lcsh:Medicine [CHIM.THER]Chemical Sciences/Medicinal Chemistry Protein Engineering Biochemistry Mice Drug Delivery Systems Phage Display Medicine and Health Sciences Bacteriophages Small interfering RNAs Enzyme-Linked Immunoassays lcsh:Science Mice Knockout Secretory Pathway Pharmaceutics Endocytosis Molecular Biology Display Techniques Nucleic acids Cell Processes Viruses Cellular Structures and Organelles Protein Binding Research Article Cell Binding Cell Physiology Recombinant Fusion Proteins Research and Analysis Methods Peptide Library Genetics Animals Humans Amino Acid Sequence Immunoassays Molecular Biology Techniques Non-coding RNA Molecular Biology Molecular Biology Assays and Analysis Techniques lcsh:R Organisms Biology and Life Sciences Cell Biology Rats Gene regulation Mice Inbred C57BL Receptors LDL Immunologic Techniques RNA lcsh:Q Gene expression Peptides Drug Delivery |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2018, 13 (2), pp.e0191052. ⟨10.1371/journal.pone.0191052⟩ PLoS ONE, 2018, 13 (2), pp.e0191052. ⟨10.1371/journal.pone.0191052⟩ PLoS ONE, Vol 13, Iss 2, p e0191052 (2018) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0191052⟩ |
| Popis: | International audience; Insufficient membrane penetration of drugs, in particular biotherapeutics and/or low target specificity remain a major drawback in their efficacy. We propose here the rational characterization and optimization of peptides to be developed as vectors that target cells expressing specific receptors involved in endocytosis or transcytosis. Among receptors involved in receptor-mediated transport is the LDL receptor. Screening complex phage-displayed peptide libraries on the human LDLR (hLDLR) stably expressed in cell lines led to the characterization of a family of cyclic and linear peptides that specifically bind the hLDLR. The VH41 1 lead cyclic peptide allowed endocytosis of payloads such as the S-Tag peptide or antibodies into cells expressing the hLDLR. Size reduction and chemical optimization of this lead peptide-vector led to improved receptor affinity. The optimized peptide-vectors were successfully conjugated to cargos of different nature and size including small organic molecules, siRNAs, peptides or a protein moiety such as an Fc fragment. We show that in all cases, the peptide-vectors retain their binding affinity to the hLDLR and potential for endocytosis. Following i.v. administration in wild type or Idlr-!-mice, an Fc fragment chemically conjugated or fused in C-terminal to peptide-vectors showed significant biodistribution in LDLR-enriched organs. We have thus developed highly versatile peptide-vectors endowed with good affinity for the LDLR as a target receptor. These peptide-vectors have the potential to be further developed for efficient transport of therapeutic or imaging agents into cells-including pathological cells-or organs that express the LDLR. |
| Databáze: | OpenAIRE |
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