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Covalent Inhibitors of Protein-Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues.

08:00 EDT 16th May 2019 | BioPortfolio

Summary of "Covalent Inhibitors of Protein-Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues."

We have recently reported on a series of Lys-covalent agents targeting the BIR3 domain of the X-linked Inhibitor of Apoptosis Protein (XIAP) using a benzamide-sulfonyl fluoride warhead. Using XIAP as a model system, we further investigated a variety of additional warheads that can be easily incorporated into binding peptides, and analyzed their ability to form covalent adducts with lysine and other amino acids, including tyrosine, histidine, serine, and threonine, using biochemical and biophysical assays. Moreover, we tested aqueous, plasma stability, cell permeability, and cellular efficacy of the most effective agents. These studies identified aryl-fluoro sulfates as likely the most suitable electrophiles to effectively form covalent adducts with Lys, Tyr, and His residues, given that these agents were cell permeable, and stable in aqueous buffer and in plasma. Our studies contain a number of general findings that open new possible avenues for the design of potent covalent PPIs antagonists.

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This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
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Medical and Biotech [MESH] Definitions

A subcategory of protein tyrosine phosphatases that are bound to the cell membrane. They contain cytoplasmic tyrosine phosphatase domains and extracellular protein domains that may play a role in cell-cell interactions by interacting with EXTRACELLULAR MATRIX components. They are considered receptor-like proteins in that they appear to lack specific ligands.

A protein motif 22 to 26 amino acids in length that binds POLY(ADP RIBOSE) polymers through non-covalent interactions. It is characterized by basic and hydrophobic residues that frequently include ALANINE; VALINE; ISOLEUCINE; or LEUCINE and flank LYSINE and ARGININE amino acids.

Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.

A Src-homology domain-containing protein tyrosine phosphatase found in the CYTOSOL of hematopoietic cells. It plays a role in signal transduction by dephosphorylating signaling proteins that are activated or inactivated by PROTEIN-TYROSINE KINASES.

A subtype of non-receptor protein tyrosine phosphatase that is closely-related to PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 1. Alternative splicing of the mRNA for this phosphatase results in the production at two gene products, one of which includes a C-terminal nuclear localization domain that may be involved in the transport of the protein to the CELL NUCLEUS. Although initially referred to as T-cell protein tyrosine phosphatase the expression of this subtype occurs widely.

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