title: Azide-alkyne cycloaddition-mediated cyclization of phosphonopeptides and their evaluation as PTP1B binders and enrichment tools.
abstract: Protein tyrosine phosphatases (PTPs) are important enzymes in health and disease, and chemical tools are crucial to understand and modulate their biological roles. PTP1B is involved in diabetes, obesity and cancer. One of the main challenges for the design of chemical tools for PTP1B is the homology to TCPTP, making tool selectivity a highly challenging task. Here, we aimed to study if azide-alkyne cycloaddition-mediated cyclization of a peptide inhibitor could increase its selectivity toward PTP1B over TCPTP, and if cyclic and linear peptide binders can be applied as enrichment tools of endogenous PTP1B. While the cyclization of the peptide binders did not improve the selectivity toward PTP1B over TCPTP, it enhanced strongly the efficiency to co-precipitate endogenous PTP1B out of cell lysates. Our results show that fine-tuning the molecular structure of peptidic pull-down baits can greatly enhance their efficiency compared to the parental peptide sequences.
authors: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Christoph
authors: C
authors: Meyer
authors: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Birgit
authors: B
authors: Hoeger
authors: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Jayanta
authors: J
authors: Chatterjee
authors: European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: koehn@embl.de.
authors: Maja
authors: M
authors: Köhn
mesh_terms: D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D061565:Cycloaddition Reaction; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000480:Alkynes; D001386:Azides; D010456:Peptides, Cyclic; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
keywords: Azide–alkyne click chemistry; Cyclic peptides; PTP1B and TCPTP; Protein tyrosine phosphatases; Pull-down baits