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Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists

Grant number: 09/14333-6
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2010
Effective date (End): February 28, 2014
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Igor Polikarpov
Grantee:Jademilson Celestino dos Santos
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:06/00182-8 - Structural biophysics of nuclear receptors and related proteins, AP.TEM


Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism and they play key roles in the control of glucose and lipid metabolism. There are three different PPAR isotypes: PPAR±, PPAR² e PPAR³. PPAR³ is a molecular target of TZD agonists, which are clinically used drugs in the control of type 2 diabetes by increasing insulin sensitivity. Whereas fibrates are drugs that act on PPAR± and are used to lower serum triglyceride levels. The most patients who have type 2 diabetes also display lipid metabolism disorders. Even with the existence of drugs that can control these metabolic disorders, the search of dual agonist for PPAR± and PPAR ³ is a major challenge in the control of metabolic syndrome, because this compound could combine both therapeutic effects in a single molecule. GL479 is a dual agonist that was synthesized based on a combination of two key pharmacophores, with the ability to bind in the both PPARs, ± and ³. Thus, this study reveals the structural basis for this dual agonist GL479 by structural determination of the complexes PPAR±-LBD:GL479 and PPAR³-LBD:GL479. The detailed analysis of these complexes showed different ligand binding modes for each receptor, however, in the both cases the GL479 interacted with the Tyr of H12. In the PPAR±-LBD structure the ligand acquired the features of full agonist and in the case of PPAR³-LBD, GL479 adopted features of a partial agonist dependent of H12 interaction. In addition to the dual agonist analysis, sixteen compounds were identified as PPAR³ ligand by docking. Three of these ligands were characterized by ThermoFluor and fluorescence polarization, which resulted in IC50 values smaller than 10 ¼M. Additionally, one of the compounds, identified by docking, was co-crystallized with PPAR³. The ligand conformation adopted would not allow it a direct interaction with the H12. These contacts were mediated by one water molecule, suggesting this compound might also act as a partial agonist, independent of H12 interaction. All these findings may be explored for the design of PPARs novel modulators with lower side effects, as well, in the exploration of dual agonists PPAR±/³ that combines the therapeutic effects in the treatment of type 2 diabetes and dyslipidemia. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DOS SANTOS, JADEMILSON CELESTINO; BERNARDES, AMANDA; GIAMPIETRO, LETIZIA; AMMAZZALORSO, ALESSANDRA; DE FILIPPIS, BARBARA; AMOROSO, ROSA; POLIKARPOV, IGOR. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma. Journal of Structural Biology, v. 191, n. 3, p. 332-340, SEP 2015. Web of Science Citations: 16.
LIBERATO, MARCELO VIZONA; GENEROSO, WESLEY CARDOSO; MALAGO, JR., WILSON; HENRIQUE-SILVA, FLAVIO; POLIKARPOV, IGOR. Crystallization and preliminary X-ray diffraction analysis of endoglucanase III from Trichoderma harzianum. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 68, n. 3, p. 306-309, MAR 2012. Web of Science Citations: 5.
TEXTOR, LARISSA C.; SANTOS, JADEMILSON C.; HIDALGO CUADRADO, NAZARET; ROIG, MANUEL G.; ZHADAN, GALINA G.; SHNYROV, VALERY L.; POLIKARPOV, IGOR. Purification, crystallization and preliminary crystallographic analysis of peroxidase from the palm tree Chamaerops excelsa. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 67, n. 12, p. 1641-1644, DEC 2011. Web of Science Citations: 1.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SANTOS, Jademilson Celestino dos. Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists. 2014. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Física de São Carlos São Carlos.

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