title: GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.
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 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" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.
authors.affiliation: Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, 70919-970 Brazil.
authors.forename: Angélica A
authors.initials: AA
authors.lastname: Amato
authors.forename: Senapathy
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Jean Z
authors.initials: JZ
authors.lastname: Lin
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Carvalho
authors.forename: Ana C M
authors.initials: AC
authors.lastname: Figueira
authors.forename: Jenny
authors.initials: J
authors.lastname: Lu
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ayers
authors.forename: Melina
authors.initials: M
authors.lastname: Mottin
authors.forename: Rodrigo L
authors.initials: RL
authors.lastname: Silveira
authors.forename: Paulo C T
authors.initials: PC
authors.lastname: Souza
authors.forename: Rosa H V
authors.initials: RH
authors.lastname: Mourão
authors.forename: Mário J A
authors.initials: MJ
authors.lastname: Saad
authors.forename: Marie
authors.initials: M
authors.lastname: Togashi
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Simeoni
authors.forename: Dulcinéia S P
authors.initials: DS
authors.lastname: Abdalla
authors.forename: Munir S
authors.initials: MS
authors.lastname: Skaf
authors.forename: Igor
authors.initials: I
authors.lastname: Polikparpov
authors.forename: Maria C A
authors.initials: MC
authors.lastname: Lima
authors.forename: Suely L
authors.initials: SL
authors.lastname: Galdino
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Pitta
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Phillips
authors.forename: Francisco A R
authors.initials: FA
authors.lastname: Neves
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017433:Protein Structure, Secondary; D045162:Thiazolidinediones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020298:U937 Cells; D015430:Weight Gain
chemical_list: C576055:5-(5-bromo-2-methoxybenzylidene)-3-(4-methyl-benzyl)thiazolidine-2,4-dione; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse