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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

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Amato, Angelica A. [1] ; Rajagopalan, Senapathy [2] ; Lin, Jean Z. [3] ; Carvalho, Bruno M. [4] ; Figueira, Ana C. M. [5] ; Lu, Jenny [2] ; Ayers, Stephen D. [2] ; Mottin, Melina [6] ; Silveira, Rodrigo L. [6] ; Souza, Paulo C. T. [6] ; Mourao, Rosa H. V. [7] ; Saad, Mario J. A. [4] ; Togashi, Marie [1] ; Simeoni, Luiz A. [1] ; Abdalla, Dulcineia S. P. [8] ; Skaf, Munir S. [6] ; Polikparpov, Igor [9, 10] ; Lima, Maria C. A. [11] ; Galdino, Suely L. [11] ; Brennan, Richard G. [12] ; Baxter, John D. [2] ; Pitta, Ivan R. [11] ; Webb, Paul [2] ; Phillips, Kevin J. [2] ; Neves, Francisco A. R. [1]
Total Authors: 25
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[1] Univ Brasilia, Lab Farmacol Mol, Dept Ciencias Farmaceut, Fac Ciencias Saude, BR-70919970 Brasilia, DF - Brazil
[2] Methodist Hosp, Res Inst, Diabet Res Ctr, Houston, TX 77030 - USA
[3] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 - USA
[4] Univ Estadual Campinas, Dept Med Interna, BR-13083887 Sao Paulo - Brazil
[5] Brazilian Assoc Synchrotron Light Technol, Natl Inst Biosci, BR-13083970 Sao Paulo - Brazil
[6] Univ Estadual Campinas, Inst Chem, BR-13084862 Sao Paulo - Brazil
[7] Univ Fed Oeste Para, Lab Bioprospeccao & Biol Expt, BR-68040070 Santarem, Para - Brazil
[8] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, BR-05508900 Sao Paulo - Brazil
[9] Univ Sao Paulo, BR-13560970 Sao Carlos, SP - Brazil
[10] Inst Fis Sao Carlos, Dept Fis, BR-13560970 Sao Carlos, SP - Brazil
[11] Univ Fed Pernambuco, Dept Antibiot, BR-50670901 Recife, PE - Brazil
[12] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 - USA
Total Affiliations: 12
Document type: Journal article
Source: Journal of Biological Chemistry; v. 287, n. 33, p. 28169-28179, AUG 10 2012.
Web of Science Citations: 53

The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPAR gamma. The structure of GQ-16 bound to PPAR gamma demonstrates that the compound utilizes a binding mode distinct from other reported PPAR gamma 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 beta-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 of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby ``ideal{''} PPAR gamma-based therapeutics stabilize the beta-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPAR gamma modulators that retain antidiabetic actions while minimizing untoward effects. (AU)

FAPESP's process: 09/14108-2 - Molecular dynamics simulations of nuclear receptors: ligand-protein free energy estimates
Grantee:Paulo Cesar Telles de Souza
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 10/08680-2 - Molecular aspectos of lignocellulosic biomass degradation: dynamics of enzymes and plant cell wall nanoarchitecture
Grantee:Rodrigo Leandro Silveira
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 10/17048-8 - Regulation of genic transactivation and transrepression mediated by nuclear receptors
Grantee:Ana Carolina Migliorini Figueira
Support type: Regular Research Grants