Pharmacological folding chaperones act as allosteric ligands of Frizzled4

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

doi:10.1038/nchembio.1770

Pharmacological folding chaperones act as allosteric ligands of Frizzled4

Nat Chem Biol. 2015 Apr;11(4):280-6. doi: 10.1038/nchembio.1770. Epub 2015 Mar 9.

Authors

Serena F Generoso¹, Mariateresa Giustiniano², Giuseppe La Regina³, Sara Bottone², Sara Passacantilli³, Salvatore Di Maro², Hilde Cassese², Agostino Bruno², Massimo Mallardo¹, Monica Dentice⁴, Romano Silvestri³, Luciana Marinelli², Daniela Sarnataro⁵, Stefano Bonatti¹, Ettore Novellino², Mariano Stornaiuolo²

Affiliations

¹ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
² Department of Pharmacy, University of Naples Federico II, Naples, Italy.
³ Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy.
⁴ Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
⁵ 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. [2] CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.

PMID: 25751279
DOI: 10.1038/nchembio.1770

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Amino Acid Motifs
Base Sequence
Cell Line, Tumor
Chemistry, Pharmaceutical / methods
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

Substances

FZD4 protein, human
Frizzled Receptors
Ligands
Molecular Chaperones
Receptors, G-Protein-Coupled
Glycerol

Associated data

PubChem-Substance/241177002
PubChem-Substance/241177003
PubChem-Substance/241177004
PubChem-Substance/241177005
PubChem-Substance/241177006
PubChem-Substance/241177007
PubChem-Substance/241177008
PubChem-Substance/241177009
PubChem-Substance/241177010
PubChem-Substance/241177011
PubChem-Substance/241177012
PubChem-Substance/241177013
PubChem-Substance/241177014
PubChem-Substance/241177015
PubChem-Substance/241177016
PubChem-Substance/241177017
PubChem-Substance/241177018
PubChem-Substance/241177019
PubChem-Substance/241177020

Grants and funding

GGP14002/TI_/Telethon/Italy