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Roberta Montanari Pagina Personale

di · May 23, 2017

Roberta Montanari

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

 

Qualifica Attuale : Ricercatore

 

Curriculum Vitae :

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
2015: EMBO Lab Management Course
2016: member of the IC Scientific Board

 

Attività di Ricerca :

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.

 

Pubblicazioni Scelte :

  1. Antonio Laghezza, Luca Piemontese, Leonardo Brunetti, Alessia Caradonna,Mariangela Agamennone, Antonella Di Pizio, Giorgio Pochetti, Roberta Montanari,Davide Capelli, Marilena Tauro, Fulvio Loiodice, and Paolo Tortorella, (2020)
    Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy in Pharmaceuticals (Basel)
  2. Montanari, R., Capelli, D., Yamamoto, K., Awaishima, H., Nishikata, K., Barendregt, A., Heck, A.J.R., Loiodice, F., Altieri, F., Paiardini, A., Grottesi, A., Pirone, L., Pedone, E., Peiretti, F., Brunel, J.M., Itoh, T., Pochetti, G. Insights into PPARγ Phosphorylation and Its Inhibition Mechanism (2020) Journal of medicinal chemistry, 63 (9), pp. 4811-4823.
  3. Capelli, D., Parravicini, C., Pochetti, G., Montanari, R., Temporini, C., Rabuffetti, M., Trincavelli, M.L., Daniele, S., Fumagalli, M., Saporiti, S., Bonfanti, E., Abbracchio, M.P., Eberini, I., Ceruti, S., Calleri, E., Capaldi, S.; Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination (2020) Frontiers in Chemistry, 7, art. n.910.
  4. Laghezza, A., Piemontese, L., Cerchia, C., Montanari, R., Capelli, D., Giudici, M., Crestani, M., Tortorella, P., Peiretti, F., Pochetti, G., Lavecchia, A., Loiodice, F.; Identification of the First PPARα/γ Dual Agonist Able to Bind to Canonical and Alternative Sites of PPARγ and to Inhibit Its Cdk5-Mediated Phosphorylation (2018) Journal of Medicinal Chemistry, 61 (18), pp. 8282-8298.
  5. Gloria Brusotti* , Roberta Montanari* , Davide Capelli , Giulia Cattaneo , Antonio Laghezza, Paolo Tortorella , Fulvio Loiodice, Franck Peiretti, Bernadette Bonardo, Alessandro Paiardini, Enrica Calleri (*equal contribution), “Betulinic acid is a PPARγ antagonist that hampers adipogenesis and promotes osteogenesis”, Scientific Reports 7(1), 5777, 2017.
  6. D.Capelli, C. Cerchia, R. Montanari, F. Loiodice, P. Tortorella, A., Laghezza, L. Cervoni, G. Pochetti and A. Lavecchia, Scientific Reports 6, 34792, 2016.
  7. Tauro M, Laghezza A, Loiodice F, Piemontese L, Caradonna A, Capelli D, Montanari R, Pochetti G, Di Pizio A, Agamennone M, Campestre C, Tortorella P. J Enzyme Inhib Med Chem. 24:1-13. 2016.
  8. Roberta Montanari, Davide Capelli, Aldo Tava, Andrea Galli, Antonio Laghezza, Paolo Tortorella, Fulvio Loiodice & Giorgio Pochetti, “Screening of saponins and sapogenins from Medicago species as potential PPARγ agonists and X-ray structure of the complex PPARγ/caulophyllogenin” (2016) Scientific Reports DOI: 10.1038/srep27658.
  9. Antonio Laghezza*, Roberta Montanari*, Antonio Lavecchia, Luca Piemontese, Giorgio Pochetti, Vito Iacobazzi, Vittoria Infantino, Davide Capelli, Michela De Bellis, Antonella Liantonio, Sabata Pierno, Paolo Tortorella, Diana Conte Camerino, Fulvio Loiodice “On the metabolically active form of metaglidasen: improved synthesis and investigation of its peculiar activity on PPARs and skeletal muscle function” (2015) ChemMedChem, Volume 10, Issue 3, 555-565. (*the authors equally contributed to this work)
  10. 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.
  11. 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.
  12. 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. 
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.

Roberta Montanari

Roberta Montanari is an expert in the field of Structural Biology and since 2009 she’s permanently employed at the Institute of Crystallography of CNR. As a Structural Biologist, she is skilled in protein expression, purification and crystallization and is experienced in data collection at synchrotron beamlines and structure determination as well. RM has more than one decade of experience and has successfully solved the structure of proteins in complex with ligand molecules. In her career, RM focused mainly on the study of the nuclear receptor PPARγ. In particular, through the use of computer-aided approaches coupled with X-ray crystallography, molecular dynamics and cell-based transcriptional assays, she contributed to the design and synthesis of a new series of ligands with different features and mode of binding. These ligands by interacting with different regions of the PPARγ LBD, confer a differentiated biological response in cell and animal models, resulting in the selective recruitment of coactivators and ultimately in the regulation of a different subset of target genes. Moreover, RM focused her interest on some PPARγ mutants associated with several known pathologies, such as lipodistrophy, T2D and colon cancer, with the aim to understand the structural/functional reason for the defective PPAR activity of these mutants and to find suitable ligands able to restore the wt activity. In the last years, RM focused on PPARγ structural changes occurring during post translational modifications. Recent studies demonstrated that CDK5-mediated phosphorylation of PPARγ may be involved in the pathogenesis of insulin-resistance, then representing an opportunity for the development of an improved generation of anti-diabetic drugs acting on PPARγ. In this context, she focused on the study of the conformational modification and the dynamic nature of this nuclear receptor during its CDK5-mediated phosphorylation. Her studies in this field were aimed to explore, through a combined biophysical and cell biology approach including HDX technology, structural changes remote from the ligand binding site. In this study she described a novel mechanism of ligand inhibition of CDK5-mediated PPARγ phosphorylation and probed that the protection of the consensus region is variably affected by ligands depending on their binding mode.