title: Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor.
abstract: In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications.
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abegg
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Giulio
authors.initials: G
authors.lastname: Gasparini
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hoch
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Anton
authors.initials: A
authors.lastname: Shuster
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Eline
authors.initials: E
authors.lastname: Bartolami
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Stefan
authors.identifier: 0000-0002-8537-8349
authors.initials: S
authors.lastname: Matile
authors.affiliation: School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
authors.forename: Alexander
authors.identifier: 0000-0001-6453-0244
authors.initials: A
authors.lastname: Adibekian
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D011990:Receptors, Transferrin / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004220:Disulfides; D011990:Receptors, Transferrin; D013876:Thiophenes; C010035:1,2-dithiolane-4-carboxylic acid