Peroxisome proliferator-activated receptors (PPARs) in the regulation of glucose and lipid metabolism: a multidisciplinary approach for the identification and characterization of new ligands to improve therapeutical interventions in diabetes, obesity[..]

 

TITLE

Peroxisome proliferator-activated receptors (PPARs) in the regulation of glucose and lipid metabolism: a multidisciplinary approach for the identification and characterization of new ligands to improve therapeutical interventions in diabetes, obesity and metabolic syndrome

STAFF

G. Pochetti
R. Montanari
B. Pascucci

KEYWORDS

diabetes, obesity, metabolic syndrome, structural biology, partial agonists

COLLABORATIONS

Laboratorio "Giovanni Galli" di Biochimica e Biologia Molecolare dei Lipidi e di Spettrometria di Massa, Università degli Studi di Milano; Dipartimento di Chimica Farmaceutica, Università degli Studi di Napoli; Dipartimento Farmaco-Chimico, Università degli Studidi Bari; Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università di L'Aquila; Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University of Tokyo (Japan).

DESCRIPTION

The epidemic rise in the prevalence of diabetes and obesity is one of the most serious public health problems in industrialized and in developing countries. Obesity is also increasing in the pediatric population and predisposes young generations to insulin resistance and diabetes. In a therapeutical perspective it is crucial to identify and characterize druggable targets to develop more effective treatments for diabetes. Among the known targets for antibiabetic agents, peroxisome proliferator-activated receptors (PPARs) have generated hopes in the last decade due to their multiple action on insulin sensitivity, lipid metabolism and inflammation. However, the recent studies on large population of patients prescribed with thiazolidinedione, known ligands of PPARγ, revealed serious side effects such as increased fat deposition, fluid retention that leads to a significant increase in the risk of myocardial infarction and of death from cardiovascular causes.


In spite of these adverse effects evidenced by the recent clinical studies, targeting PPARs has shown proven benefits in different experimental models, thus a new generation of molecules targeting one or more subtypes of these receptors should be designed in such a way to exploit their therapeutic potential but avoiding the known side-effects. A rationale approach to achieve this goal is the careful evaluation of the structure-activity relationship of a given ligand in the complex with the receptor. In this context, X-ray crystallography, molecular dynamics and in silico studies, coupled with state-of-the-art technologies to evaluate the biological activity of PPAR ligands, is a powerful tool for the design of a new series of molecules targeting these receptors with a more favorable pharmaco-toxycological profile.

 

At this regard, we have recently evidenced new structural features of PPARs in the complex with a new series of ligands (1-4) that confer a peculiar biological response in cell and animal models. In particular, our recent X-ray studies identified novel ligand-receptor interaction modalities that represent a new hallmark of the partial agonism behavior of certain ligands, a feature that could be very useful to maintain the therapeutical action diminuishing the side effects.

(1) POCHETTI G., NICO M, 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 γ Binding of Two Ureidofibrate-Like Enantiomers by Molecular Dynamics, Cofactor Interaction Analysis, and Site-Directed Mutagenesis". J. Med. Chem., 2010, 53 (11), pp 4354–4366

(2) FRACCHIOLLA G., LAGHEZZA A., PIEMONTESE L., TORTORELLA P., MAZZA F., MONTANARI R., POCHETTI G., LAVECCHIA A., NOVELLINO E., PIERNO S., CONTE CAMERINO D. AND LOIODICE F. "New 2-Aryloxy-3-phenyl-propanoic Acids As Peroxisome Proliferator-Activated Receptors α/γ Dual Agonists with Improved Potency and Reduced Adverse Effects on Skeletal Muscle Function". J. Med. Chem., 2009, 52, pp 6382-6393

(3) 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., POCHETTI G. "Crystal structure of the PPAR-gamma 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, pp 7768-7776

(4) 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 gamma ligand-binding domain in the complex with two enantiomeric ligands". J. Biol. Chem, 2007, 282, pp 17314-17324

 

Peroxisome proliferator-activated receptors (PPARs) in the regulation of glucose and lipid metabolism: a multidisciplinary approach for the identification and characterization of new ligands to improve therapeutical interventions in diabetes, obesity and metabolic syndrome - Img

Figure: Our ligand LT175 occupies a new region of the hydrophobic pocket of PPARγ that could be exploited for drug design.

 

CONTACTS


Giorgio Pochetti
Email: giorgio.pochettiATic.cnr.it
Tel.: +390690672633

 

Last Updated (Tuesday, 21 December 2010 16:06)