Pharmacological folding chaperones act as allosteric ligands of Frizzled4

Nature Chemical Biology
Serena F GenerosoMariano Stornaiuolo

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.

References

Feb 22, 2001·Annual Review of Physiology·J P Morello, D G Bichet
Aug 13, 2002·Nature Genetics·Johane RobitailleMark E Samuels
Dec 20, 2003·Nature·Christopher M Dobson
Dec 20, 2003·Nature·Roberto Sitia, Ineke Braakman
Jun 10, 2005·Neuron·Jérôme SallettePierre Jean Corringer
Dec 2, 2005·Journal of the American Society of Nephrology : JASN·Virginie BernierDaniel G Bichet
Feb 17, 2006·Cellular Signalling·Hsien-yu WangCraig C Malbon
Nov 28, 2006·Frontiers in Bioscience : a Journal and Virtual Library·Jordane MalaterreTheo Mantamadiotis
Aug 9, 2007·International Journal of Cancer. Journal International Du Cancer·Guillaume ChatelRosita Winkler
Sep 22, 2007·Trends in Pharmacological Sciences·Gunnar Schulte, Vítezslav Bryja
Jul 2, 2008·Neoplasia : an International Journal for Oncology Research·Koji UenoYuji Hinoda
Apr 23, 2009·The Journal of Biological Chemistry·David GrandyJie J Zheng
Oct 9, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Cheng XiaoHenry A Lester
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Claire L NewtonRobert P Millar
Jul 22, 2011·Nature·F Ulrich HartlManajit Hayer-Hartl
Nov 15, 2011·Recent Patents on Endocrine, Metabolic & Immune Drug Discovery·Alfredo Ulloa-Aguirre, P Michael Conn
Mar 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Daniele V F TaurielloMadelon M Maurice
May 15, 2012·Journal of Structural Biology·Stephan RadnerMariano Stornaiuolo
May 24, 2012·The EMBO Journal·Paul Polakis
Jun 2, 2012·Science·Claudia Y JandaK Christopher Garcia
Jul 4, 2012·Proceedings of the National Academy of Sciences of the United States of America·Austin GurneyTimothy Hoey
Sep 25, 2012·Cold Spring Harbor Perspectives in Biology·Zachary F ZimmermanAndy J Chien
Sep 29, 2012·Current Pharmaceutical Design·Andrey Voronkov, Stefan Krauss
Nov 20, 2012·Sub-cellular Biochemistry·Guadalupe Maya-NúñezP Michael Conn
Dec 5, 2012·Cold Spring Harbor Perspectives in Biology·Bryan T MacDonald, Xi He
Feb 8, 2013·Journal of the American Chemical Society·Reggy EkkebusHuib Ovaa
May 3, 2013·Nature·Chong WangRaymond C Stevens
May 23, 2013·Nature Communications·Mariano StornaiuoloTitia K Sixma

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Citations

Jul 9, 2016·Molecular and Cellular Endocrinology·Jo Ann JanovickP Michael Conn
May 17, 2017·Chemistry : a European Journal·Carlo DiaferiaAntonella Accardo
Mar 8, 2017·Molecular BioSystems·Min Hyeon Shin, Hyun-Suk Lim
Mar 1, 2017·American Journal of Respiratory and Critical Care Medicine·Wioletta Skronska-WasekMelanie Königshoff
Nov 15, 2017·International Journal of Molecular Sciences·H M Mazhar AsjadChristian Nanoff
Feb 15, 2018·Physiological Reviews·Ya-Xiong Tao, P Michael Conn
May 19, 2018·Nature Communications·Yuanyuan ChenKrzysztof Palczewski
Dec 17, 2017·Pharmacological Reviews·Sébastien FoulquierW Matthijs Blankesteijn
Jun 24, 2015·The Journal of Biological Chemistry·Patrick R GentryArthur Christopoulos
Jun 1, 2018·Cancer Cell International·Hanin AlamirDeema Hussein
Mar 21, 2018·Proceedings of the National Academy of Sciences of the United States of America·Daniel MattleRoger J P Dawson
Oct 9, 2019·Molecular Pharmacology·Pawel KozielewiczGunnar Schulte
Jan 23, 2020·Nature Communications·Paweł KozielewiczGunnar Schulte
Nov 22, 2020·Pharmacological Reviews·Torsten Schöneberg, Ines Liebscher
Feb 13, 2020·Journal of Medicinal Chemistry·Yuguang ZhaoE Yvonne Jones

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