title: Activatable cell penetrating peptide-peptide nucleic acid conjugate via reduction of azobenzene PEG chains.
abstract: The use of stimuli-responsive bioactive molecules is an attractive strategy to circumvent selectivity issues in vivo. Here, we report an activatable cell penetrating peptide (CPP) strategy ultimately aimed at delivering nucleic acid drugs to the colon mucosa using bacterial azoreductase as the local reconversion trigger. Through screening of a panel of CPPs, we identified a sequence (M918) capable of carrying a nucleic acid analogue payload. A modified M918 peptide conjugated to a peptide nucleic acid (PNA) was shown to silence luciferase in colon adenocarcinoma cells (HT-29-luc). Reversible functionalization of the conjugate's lysine residues via an azobenzene self-immolative linkage abolished transfection activity, and the free CPP-PNA was recovered after reduction of the azobenzene bond. This activatable CPP conjugate platform could find applications in the selective delivery of nucleic acid drugs to the colon mucosa, opening therapeutic avenues in colon diseases.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ) , Zurich 8093, Switzerland.
authors.forename: Soo Hyeon
authors.initials: SH
authors.lastname: Lee
authors.forename: Elena
authors.initials: E
authors.lastname: Moroz
authors.forename: Bastien
authors.initials: B
authors.lastname: Castagner
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000595:Amino Acid Sequence; D001391:Azo Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D020135:Peptide Nucleic Acids / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D014162:Transfection
chemical_list: D001391:Azo Compounds; D057846:Cell-Penetrating Peptides; D020135:Peptide Nucleic Acids; D011092:Polyethylene Glycols; C009850:azobenzene