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Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins
Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria.;Univ Nat Resources & Life Sci BOKU, Dept Agobiotechnol, Ctr Analyt Chem, Vienna, Austria..
Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria..
Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2017 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 5, article id 73Article in journal (Refereed) Published
Abstract [en]

Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomally synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates. For example, plant-derived circular peptides called cyclotides have recently attracted much attention due to their immunosuppressive effects and oral activity in the treatment of multiple sclerosis in mice, but their molecular target has hitherto not been reported. In this study, a chemical proteomics approach using photo-affinity crosslinking was developed to determine a target for the circular peptide [T20K]kalata B1. Using this prototypic nature-derived peptide enabled the identification of a possible functional modulation of 14-3-3 proteins. This biochemical interaction was validated via competition pull down assays as well as a cellular reporter assay indicating an effect on 14-3-3-dependent transcriptional activity. As proof of concept, the presented approach may be applicable for target elucidation of various cyclic peptides and mini-proteins, in particular cyclotides, which represent a promising class of molecules in drug discovery and development.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2017. Vol. 5, article id 73
Keywords [en]
cyclotides, cyclic protein, chemical proteomics, peptide-protein interaction, photo-affinity labeling
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-338516DOI: 10.3389/fchem.2017.00073ISI: 000412726000001PubMedID: 29075625OAI: oai:DiVA.org:uu-338516DiVA, id: diva2:1173892
Funder
Australian Research Council, FT140100730Available from: 2018-01-15 Created: 2018-01-15 Last updated: 2018-01-15Bibliographically approved

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