Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins

Frontiers in Chemistry
Roland HellingerChristian W Gruber

Abstract

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...Continue Reading

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Citations

Apr 24, 2019·Biomedicines·Julio A Camarero, Maria Jose Campbell
Oct 1, 2021·ACS Chemical Biology·Roland HellingerChristian W Gruber

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Datasets Mentioned

BETA
PXD004798

Methods Mentioned

BETA
affinity purification
transfection
ELISA
pull
electrophoresis
pull down
NMR
pull downs

Software Mentioned

GraphPad Prism
ImageJ
Mascot
Proteinscape
Compass Data Analysis
oTOF control

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