Journal Article

Pharmacological folding chaperones act as allosteric ligands of Frizzled4

Cassese, Hilde, Marinelli, Luciana, Giustiniano, Mariateresa, Stornaiuolo, Mariano, Dentice, Monica, Passacantilli, Sara, Bonatti, Stefano, Sarnataro, Daniela, Di Maro, Salvatore, Generoso, Serena F, Bottone, Sara, Silvestri, Romano, La Regina, Giuseppe, Mallardo, Massimo, Bruno, Agostino, Novellino, Ettore

2015

Overview

Several GPCRs have ligands that act as pharmacological chaperones that rescue function of mutated receptors. This formed the basis of a screening strategy to identify new ligands for Frizzled4 that act allosterically at an effector domain to inhibit β-catenin signaling. Upon binding, ligands can chaperone their protein targets by preventing them from misfolding and aggregating. Thus, an organic molecule that works as folding chaperone for a protein might be its specific ligand, and, similarly, the chaperone potential could represent an alternative readout in a molecular screening campaign toward the identification of new hits. Here we show that small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor bind and modulate wild-type Fz4, representing what are to our knowledge the first organic ligands of this until-now-undruggable GPCR. The novelty and the advantages of the screening platform, the allosteric binding site addressed by these new ligands and the mechanism they use to modulate Fz4 suggest new avenues for development of inhibitors of the Wnt–β-catenin pathway and for drug discovery.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/47 / 101/58 / 14 / 14/19 / 45/70 / 631/154/1435 / 631/535 / 631/80/313 / 631/92/470/2284 / 96/106 / 96/109 / 96/98 / Allosteric Site / Amino Acid Motifs / Base Sequence / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Cell Line, Tumor / Chemistry / Chemistry, Pharmaceutical - methods / Chemistry/Food Science / Dose-Response Relationship, Drug / Drug Design / Frizzled Receptors - chemistry / Glycerol - chemistry / HEK293 Cells / HeLa Cells / Humans / Ligands / Microscopy, Fluorescence / Molecular Chaperones - chemistry / Molecular Sequence Data / Mutagenesis / Protein Binding / Protein Folding / Receptors, G-Protein-Coupled - chemistry