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

PloS One
Marion DavidMichel Khrestchatisky

Abstract

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 VH411 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 ldlr-/- mice, an Fc...Continue Reading

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Citations

Mar 3, 2021·Nature Reviews. Drug Discovery·Georg C TerstappenWandong Zhang
Aug 21, 2021·Communications Biology·Angélina AcierFabienne Guillaumond

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Methods Mentioned

BETA
PCR
transfection
ELISA
Protein Assay
pull
electrophoresis
phage display
FACS
High Performance Liquid Chromatography
chip

Software Mentioned

ImageJ
Biacore T200 Evaluation
Image J
JaCoP
ClustalW
Zen
BD FACSDiva

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