GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.

The Journal of Biological Chemistry
Angélica A AmatoFrancisco A R Neves

Abstract

The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity ...Continue Reading

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Aug 23, 2000·The Journal of Clinical Investigation·J M Olefsky
Jan 4, 2001·The Journal of Nutrition·R F Morrison, S R Farmer
Jun 8, 2001·Annual Review of Biochemistry·T M WillsonS A Kliewer
Jan 17, 2003·Obesity Research·Lenka JanderováSteven R Smith
Jul 28, 2004·Trends in Biochemical Sciences·Laszlo Nagy, John W R Schwabe
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Dec 18, 2004·Bioorganic & Medicinal Chemistry Letters·John J ActonHarold B Wood
Jun 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hui ZhangTianxin Yang
Jun 28, 2005·Nucleic Acids Research·John C GordonAlexey Onufriev
Jul 26, 2005·European Journal of Medicinal Chemistry·R H MourãoI R Pitta
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jan 13, 2006·Methods in Enzymology·Claudia S Maier, Max L Deinzer
Apr 13, 2006·The Journal of Clinical Endocrinology and Metabolism·Ann V SchwartzSteven R Cummings
Oct 24, 2006·Endocrine Reviews·Maria E Trujillo, Philipp E Scherer
Mar 17, 2007·Diabetes Care·Subhashini YaturuSushil K Jain
Apr 24, 2007·European Journal of Medicinal Chemistry·Lúcia Fernanda C da Costa LeiteIvan da Rocha Pitta
May 23, 2007·The New England Journal of Medicine·Steven E Nissen, Kathy Wolski
Aug 24, 2007·BMC Bioinformatics·Leandro MartínezJosé Mario Martínez
Aug 25, 2007·The Journal of Clinical Investigation·Ja-Young KimPhilipp E Scherer
Oct 17, 2007·Structure·John B BruningPatrick R Griffin
Dec 2, 2008·Nature·Vikas ChandraFraydoon Rastinejad
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jul 24, 2010·Nature·Jang Hyun ChoiBruce M Spiegelman
May 3, 2011·Nature Medicine·Karen K RyanRandy J Seeley
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus

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Citations

Oct 16, 2015·Current Hypertension Reports·Madeliene StumpCurt D Sigmund
Mar 31, 2016·Assay and Drug Development Technologies·Nina ProkophJianming Liu
Sep 24, 2015·ACS Medicinal Chemistry Letters·Alice AsteianTheodore M Kamenecka
Oct 6, 2015·PPAR Research·Alice J Kroker, John B Bruning
Aug 28, 2015·Future Medicinal Chemistry·Daniel MerkManfred Schubert-Zsilavecz
Jan 13, 2015·Expert Opinion on Therapeutic Patents·Nisheeth C DesaiAmit Dodiya
Nov 28, 2012·Chemical & Pharmaceutical Bulletin·Jason Taylor SchottHubrecht Johan Peter de Lijser
Jun 9, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shuibang WangRobert L Danner
Dec 28, 2016·International Journal of Molecular Sciences·Melina MottinMunir S Skaf
Jan 15, 2015·Biochimica Et Biophysica Acta·Guilherme Martins SantosAngélica Amorim Amato
Jan 24, 2017·Chemical Biology & Drug Design·Diogo Rodrigo Magalhaes MoreiraCristiane Flora Villarreal
Dec 19, 2016·European Journal of Medicinal Chemistry·Sabina Yasmin, Venkatesan Jayaprakash
Feb 18, 2018·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Jacqueline C SilvaDulcineia S P Abdalla
Apr 1, 2015·Molecular and Cellular Biology·Chaowei WuMichael J Garabedian
Apr 6, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michel Leandro CamposRoberto Pontarolo
Jan 8, 2020·Clinical and Experimental Pharmacology & Physiology·Odair Alves SilvaGlória Pinto Duarte
Dec 26, 2018·Antioxidants & Redox Signaling·Victor TsengC Michael Hart
Aug 14, 2019·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Masashi Mukohda
May 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yuki UtsugiYusaku Miyamae
Jul 23, 2020·PPAR Research·Åsmund Kaupang, Trond Vidar Hansen
Jun 14, 2018·International Journal of Molecular Sciences·Reinhard Brunmeir, Feng Xu
Aug 24, 2019·Advances in Wound Care·Jacqueline C SilvaDulcineia S P Abdalla
Dec 18, 2020·Frontiers in Endocrinology·Marieli Mariano Gonçalves DiasAna Carolina Migliorini Figueira
Oct 30, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Muluken Altaye AyzaDerbew Fikadu Berhe
May 5, 2021·Journal of Molecular Graphics & Modelling·Karina de PaulaAlessandro S Nascimento
Aug 3, 2021·The Journal of Biological Chemistry·Rebecca L FrkicJohn B Bruning
Feb 19, 2015·Journal of Chemical Information and Modeling·Sirish Kaushik LakkarajuAlexander D MacKerell
Jul 19, 2019·Journal of Structural Biology·H V Ribeiro FilhoA C M Figueira
Mar 4, 2015·Journal of Medicinal Chemistry·Santiago Garcia-VallvéMiquel Mulero
Aug 30, 2021·European Journal of Medicinal Chemistry·Zheng LiLuyong Zhang
Sep 30, 2021·International Journal of Radiation Biology·Mariana Brayner CavalcantiEdvane Borges da Silva

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