PPARs
Proliferator-Activated Receptors (PPARs) belong to the class of
nuclear receptors superfamily.
They are ligand-dependent transcriptional factors involved in the
control and expression of several genes implicated in glucidic and lipidic
homeostasis and energetic balance. In humans, three different isoforms have
been identified: PPARα, PPARβ/δ, and PPARγ. They have different tissue distribution
as well as different binding affinity for ligands and recruitment ability of
coactivators and corepressors. PPARα is mostly involved in the control of lipidic catabolism.
PPARβ/δ is ubiquitously distributed, with a physiological profile similar but non
interchangeable with PPARα. PPARγ is expressed in adipose tissue, where it induces
lipogenesis and fat storage, and in skeletal muscle, where it improves insulin sensitivity.
PPARs, therefore, represent valuable therapeutic targets for the treatment of both hyperlipidemia
and insulin resistance in metabolic disorders.
Many efforts have been directed toward the combination, in a unique chemical entity,
of the insulin-sensitizing effect of PPARγ activation with the additional
lipid-modifying activity of other PPAR subtypes.
Therefore, the development of novel selective PPAR modulators, dual and pan PPAR
agonists constitute a promising approach.
Recent Publications
Laghezza, A.; Falbo, E.; Gilardi, F.; Thomas, A.; Brunetti, L.; Leuci, R.; Piemontese, L.; Tortorella, P.; Biswas, A.; Singh, R. P.; Pattnaik, A. K.; Jayaprakash, V.; Tambe, S.; Ca, S.; Wackerlig-Damle, J.; Paoli, P.; Loiodice, F.; Lavecchia, A.
A new potent and selective peroxisome proliferator-activated receptor alpha partial agonist displays anti-steatotic effects In vitro and behaves as a safe hypolipidemic and hypoglycemic agent in a diabetic mouse model. Eur J Med Chem. 2025, 289, 117494.
Laghezza, A.; Cerchia, C.; Genovese, M.; Montanari, R.; Capelli, D.; Wackerlig, J.; Simic, S.; Falbo, E.; Pecora, L.; Leuci, R.; Brunetti, L.; Piemontese, L.; Tortorella, P.; Biswas, A.; Singh, R.P.; Tambe, S.; Sudeep, CA; Pattnaik, AK; Jayaprakash, V.; Paoli, P.; Lavecchia, A.; Loiodice, F.
A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties. Eur. J. Med. Chem., 2024, 116567.
Laghezza, A.; Cerchia, C.; Genovese, M.; Leuci, R.; Pranzini, E.; Santi, A.; Brunetti, L.; Piemontese, L.; Tortorella, P.; Biswas, A.; Singh, R.P.; Tambe, S.; Ca, S.; Pattnaik, A.K.; Jayaprakash, V.; Paoli, P.; Lavecchia, A.; Loiodice, F. A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition. J. Med. Chem. 2023, 66, 5, 3566–3587.
Capelli, C.; Cerchia, C.; Montanari,R.; Loiodice, F.; Tortorella, P.; Laghezza, A.; Pochetti, G.;
Lavecchia, A.Structural Basis for PPAR Partial or Full Activation Revealed by a
Novel Ligand Binding Mode.Sci. Rep. 2016, 6, 34792.
Zurlo, D.; Ziccardi, P.; Votino, C.; Cerchia, C.; Dal Piaz, F.; Dallavalle, S.; Moricca, S.;
Novellino, E.; Lavecchia, A.; Colantuoni, V.; Lupo, A. Cladosporols A and B from
Cladosporium Tenuissimum Inhibit Proliferation and Induce Apoptosisthrough the Modulation of
Peroxisome Proliferator-activated Receptorγ. Biochem. Pharm. 2016, 108, 22-35.
Laghezza, A.; Montanari, R.; Lavecchia, A.; Piemontese, L.; Pochetti, G.; Iacobazzi, V.;
Infantino, V.; Capelli, D.; De Bellis, M.; Liantonio, A.; Pierno, S.; Tortorella, P.; Conte Camerino, D.;
Loiodice, F. On the Metabolically Active Form of Metaglidasen:
Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator-Activated Receptors
(PPARs) and Skeletal Muscle Function. ChemMedChem 2015, 10, 555-565.
Gilardi, F.; Giudici, M.; Mitro, N.; Maschi, O.; Guerrini, U.; Rando, G.; Maggi, A.; Cermenati, G.;
Laghezza, A.; Loiodice, F.; Pochetti, G.; Lavecchia, A.; Caruso, D.; De Fabiani, E.; Bamberg, K.;
Crestani, M.LT175 is a novel PPARα/γ ligand with potent insulinsensitizingeffects and reduced adipogenic properties.
J. Biol. Chem. 2014, 289, 6908-6920.
Gilardi, F.; Giudici, M.; Mitro, N.; Maschi, O.; Guerrini, U.;
Rando, G.; Maggi, A.; Cermenati, G.; Laghezza, A.; Loiodice, F.;
Pochetti, G.; Lavecchia, A.; Caruso, D.; De Fabiani, E.; Bamberg, K.;
Crestani, M. LT175 is a novel PPARα/γ ligand with potent insulin sensitizing
effects and reduced adipogenic properties. J. Biol. Chem. 2014, 289, 6908-6920.
Laghezza, A.; Pochetti, G.; Lavecchia, A.; Fracchiolla, G.; Faliti, S.;
Piemontese, L.; Montanari, R.; Di Giovanni, C.; Iacobazzi, V.; Infantino, V.;
Tortorella, P.; Loiodice, F. New 2-Aryloxy-3-phenyl-propanoic Acids as Potent
Peroxisome Proliferator-Activated Receptors a/γ Dual Agonists Able To Upregulate the
Mitochondrial Carnitine Shuttle System Gene Expression. J. Med. Chem. 2013, 56, 60−72.
Pochetti, G.; Mitro, N.; Lavecchia, A.; Gilardi, F.; Besker, N.;
Scotti, E.; Aschi, M.; Re, N.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.;
Montanari, R.; Novellino, E.; Mazza, F.; Crestani, M.; Loiodice, F.
Structural Insight into Peroxisome Proliferator-Activated Receptor
Gamma Binding of Two Ureidofibrate-Like Enantiomers by Molecular Dynamics,
Cofactor Recruitment Analysis and Site-Directed Mutagenesis. J. Med. Chem. 2010, 53, 4354-4366.
Montanari, R.; Saccoccia, F.; Scotti, E.; Crestani, M.; Godio, C.;
Gilardi, F.; Loiodice, F.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.;
Lavecchia, A.; Novellino, E.; Mazza, F.; Aschi, M.; Pochetti, G.
Crystal structure of the peroxisome proliferator-activated receptor
gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist:
a new region of the hydrophobic pocket could be exploited for drug design. J. Med. Chem. 2008, 51, 7768-7776.
Pochetti, G.; Godio, C.; Mitro, N.; Caruso, D.; Galmozzi, A.; Scurati, S.;
Loiodice, F.; Fracchiolla, G.; Tortorella, P.; Laghezza, A.; Lavecchia, A.;
Novellino, E.; Mazza, F.; Crestani, M. Insights into the Mechanism of Partial
Agonism. Crystal Structures of the Peroxisome Proliferator-Activated Receptor
Ligand-Binding Domain in the Complex with two Enantiomeric Ligands. J.
Biol. Chem. 2007, 282, 17314-17324.
