Roberta Montanari

 

Roberta MontanariRoberta Montanari

Tel +39 06 90672618
Fax +39 06 90672630
E-mail : roberta.montanariATic.cnr.it
Address : CNR - Institute of Crystallography, sede di Monterotondo
Via Salaria - km 29,300
Area della Ricerca ROMA1
00015 Monterotondo Stazione, Roma ITALY

 

 

 

Present position :


- Researcher

 

Short CV :

2001: Laurea Diploma cum laude in Pharmacy, University of Roma "La Sapienza";
2002: Grant from CNR, Institute of Crystallography;
2002 - 2005: Researcher at CNR, Institute of Chemical Methodologies;
2008: PhD in Medicinal Sciences, University of Roma "La Sapienza";
2008: EMBO fellowship, Dept. of Biochemistry - University of Leicester - UK;
2009: Postdoctoral grant, Institute of Crystallography IC-CNR;
2009: Permanent position as researcher, Institute of Crystallography IC-CNR.
2012: Invited researcher at Showa Pharmaceutical University of Tokyo
2014: Second Level Master Degree in Bionformatics.

 

Research Activity :


a) Design of new, potent and selective inhibitors of matrix metalloproteinases by crystallographic techniques, molecular modelling and molecular dynamics.
MMPs are zinc-endopeptidases involved in many physiological processes such as ovulation, embryogenesis, cellular differentiation and wound healing. Over-expression of MMPs or inadequate control by their natural inhibitors are associated with a variety of pathological conditions such as psoriasis, multiple sclerosis, osteoarthritis, rheumatoid arthritis, osteoporosis, tumor growth and metastasis. Synthetic inhibitors of the first generation include the potent hydroxamates. However they are affected by lack of selectivity and toxicity. Our research group have developed less potent but more selective inhibitors, such as phosphonates, whose crystal structure in the active site of MMP-8 have been determined by X-ray crystallography. Nowadays, new generation inhibitors not chelating the catalytic zinc ion have been developed by pharmaceutical companies for MMP-13 and MMP-12. Recently, we solved the structures of two complexes of MMP-8 with the first potent and selective non-zinc chelating inhibitors.

b) Design and X-ray characterization of novel ligands of the nuclear receptors PPARs (Peroxisome Proliferator-Activated Receptors).
PPARs are transcriptional factors regulating the lipidic metabolism and the glucose homeostasis. They are target of synthetic ligands for the treatment of type 2 diabetes and obesity. For instance, the thiazolidinedione (TZD) anti-diabetic agents are PPARgamma agonists whose insulin-sensitizing action is well known in the adipose tissues. However, despite their wide prescription PPAR-activating drugs revealed unwanted side effects that cannot be underestimated. For this reasons novel PPARgamma ligands have been identified that are superior therapeutic agents for metabolic disease, such as PPARalpha/gamma dual agonists and PPAR selective modulators (SPPARMs) which present fewer adverse effects.
In the last years our group developed novel PPARalpha/gamma dual agonists with improved therapeutic efficacy and reduced side effects. X-ray studies and MD simulations on the complexes between PPARs and these ligands allowed an explanation at molecular level for their different pharmacological profile and allowed to get insight into the mechanism of partial agonism in PPARs. Moreover, we discovered new modes of binding of the ligands that could be exploited for a more fine modulation of the transactivation activity.

 

Selected publications :

1. Lori, C., Pasquo, A., Montanari, R., Capelli, D., Consalvi, V., Chiaraluce, R., Cervoni, L., Loiodice, F., Laghezza, A., Aschi, M., Giorgi, A.,Pochetti, G. STRUCTURAL BASIS OF THE TRANSACTIVATION DEFICIENCY OF THE HUMAN PPARGamma F360L MUTANT ASSOCIATED WITH FAMILIAL PARTIAL LIPODYSTROPHY. Acta Crystallographica Section D: Biological Crystallography
Volume 70, Issue 7, July 2014, Pages 1965-1976
2.Calleri, E., Pochetti, G., Dossou, K.S.S., Laghezza, A., Montanari, R., Capelli, D., Prada, E., Loiodice, F., Massolini, G., Bernier, M., Moaddel, R. RESVERATROL AND ITS METABOLITES BIND TO PPARs. ChemBioChem Volume 15, Issue 8, 26 May 2014, Pages 1154-1160
3. Temporini, C., Pochetti, G., Fracchiolla, G., Piemontese, L., Montanari, R., Moaddel, R., Calleri, E. (2013). OPEN TUBULAR COLUMNS CONTAINING THE IMMOBILIZED LIGAND BINDING DOMAIN OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ALPHA AND GAMMA FOR DUAL AGONISTS CHARACTERIZATION BY FRONTAL AFFINITY CHROMATOGRAPHY WITH MASS SPECTROMETRY DETECTION. Journal of Chromatography A, 1284, 36-43.  
4. Laghezza, A., Pochetti, G., Lavecchia, A., Fracchiolla, G., Faliti, S., Piemontese, L., Montanari,R.,. . . Loiodice, F. (2013). NEW 2-(ARYLOXY)-3-PHENYLPROPANOIC ACIDS AS PEROXISOME PROLIFERATOR- ACTIVATED RECEPTOR ALPHA/GAMMA DUAL AGONISTS ABLE TO UPREGULATE MITOCHONDRIAL CARNITINE SHUTTLE SYSTEM GENE EXPRESSION. Journal of Medicinal Chemistry, 56(1), 60-72.
5. Calleri, E., Fracchiolla, G., Montanari, R., Pochetti, G., Lavecchia, A., Loiodice, F., Temporini, C. (2012). FRONTAL AFFINITY CHROMATOGRAPHY WITH MS DETECTION OF THE LIGAND BINDING DOMAIN OF PPARGAMMA RECEPTOR: LIGAND AFFINITY SCREENING AND STEREOSELECTIVE LIGAND-MACROMOLECULE INTERACTION. Journal of Chromatography A, 1232, 84-92.
6. Porcelli, L., Gilardi, F., Laghezza, A., Piemontese, L., Mitro, N., Azzariti, A., Montanari,R.,…Loiodice, F. (2012). SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF UREIDOFIBRATE-LIKE DERIVATIVES ENDOWED WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ACTIVITY. Journal of Medicinal Chemistry, 55(1), 37-54.
7. Fracchiolla, G., Laghezza, A., Piemontese, L., Parente, M., Lavecchia, A., Pochetti, G., Montanari, R., . . . Loiodice, F. (2012). SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR INVESTIGATION OF FLUORINATED PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ALPHA/GAMMA DUAL AGONISTS. Bioorganic and Medicinal Chemistry, 20(6), 2141-2151.
8. Pochetti, G., Mitro, N., Lavecchia, A., Gilardi, F., Besker, N., Scotti, E., Montanari,R.,. . . Loiodice, F. (2010). STRUCTURAL INSIGHT INTO PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA BINDING OF TWO UREIDOFIBRATE-LIKE ENANTIOMERS BY MOLECULAR DYNAMICS, COFACTOR INTERACTION ANALYSIS, AND SITE-DIRECTED MUTAGENESIS. Journal of Medicinal Chemistry, 53(11), 4354-4366.
9. Fracchiolla, G., Laghezza, A., Piemontese, L., Tortorella, P., Mazza, F., Montanari, R., . . . Loiodice, F. (2009). NEW 2-ARYLOXY-3-PHENYL-PROPANOIC ACIDS AS PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ALPHA/GAMMA DUAL AGONISTS WITH IMPROVED POTENCY AND REDUCED ADVERSE EFFECTS ON SKELETAL MUSCLE FUNCTION. Journal of Medicinal Chemistry, 52(20), 6382-6393.
10. Pochetti, G., Montanari, R., Gege, C., Chevrier, C., Taveras, A. G., & Mazza, F. (2009). EXTRA BINDING REGION INDUCED BY NON-ZINC CHELATING INHIBITORS INTO THE S 1 SUBSITE OF MATRIX METALLOPROTEINASE 8 (MMP-8). Journal of Medicinal Chemistry, 52(4), 1040-1049.
11. Montanari, R., Saccoccia, F., Scotti, E., Crestani, M., Godio, C., Gilardi, F., . . . Pochetti, G. (2008). 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. Journal of Medicinal Chemistry, 51(24), 7768-7776.
12. Ursini, O., Lilla, E., & Montanari, R. (2006). THE INVESTIGATION ON CATIONIC EXCHANGE CAPACITY OF ZEOLITES: THE USE AS SELECTIVE ION TRAPPERS IN THE ELECTROKINETIC SOIL TECHNIQUE. Journal of Hazardous Materials, 137(2), 1079-1088.

 

Last Updated (Thursday, 02 April 2015 16:57)