Giorgio Pochetti

 

Giorgio PochettiGiorgio Pochetti

Tel +39 06 90672633/627
Fax +39 06 90672630
E-mail : giorgio.pochettiATic.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 :


- Permanent position as Researcher at CNR, Institute of Crystallography, sede di Monterotondo, Area della Ricerca ROMA1, Roma.

 

Short CV :

 

1984 - Permanent position as researcher of Institute of Crystallography (C.N.R. of Rome).

1988 - Fellowship on protein crystallography, Chemistry Dept. (Prof. G.Dodson), University of York, UK

1991 - Supervisor for a Pharmaceutical Chemistry Degree (a.a. 1991-1992).

1994 - Working at the "Progetto Strategico: Tecnologie Chimiche Innovative" funded by CNR, entitled "Design by molecular modeling, synthesis and structural study of new and potent inhibitors of matrix metalloproteases".

1995 - Tutor in the "Experimental School of Crystallography" held in Monterotondo (Rome).

1995 - Responsible of a Research Project of IC : "Natural and synthetic Oligopeptides".

1995 - Supervisor for a Pharmaceutical Chemistry Degree.

1998-2000 - Responsible of the national CNR Project "Biotechnologies" : "Design, synthesis and structure-activity relationships of new peptide inhibitors of Zn-proteinases involved in inflammatory processes".

2006 - "CNR Short term mobility" in the laboratory of molecular biology of Dr. John Schwabe (LMB-MRC Cambridge (UK)) working on a research project on Nuclear Receptors. During this time he acquired experience on protein expression and purification and on new experimental techniques (Biacore, Robot for protein crystallization trials). He gave two seminars at the MRC of Cambridge and at the Biochemistry Department of the University of Bristol.

2006 - He gave a seminar at the University of L'Aquila entitled "Molecular basis of partial agonism: crystal structure of PPARgamma in the complex with two enantiomeric ligands" as expert in the field of nuclear receptors.

2006-8 - Supervisor for a PhD in Pharmaceutical Sciences (XXI° cycle - 2006-07 and 2007-08).

2007 - Supervisor for a Chemistry Degree (2007-08)

2007 - Responsible of the RSTL Research "Non-coding DNA Structures" financed by CNR in 2007.

2007 - Member of the Commission "Prize in memory of Dr. Enrico Gavuzzo".

2008 - Supervisor for two Pharmaceutical Biotecnologies Degrees

2009 - He gave two seminars at the University of Bari for PhD students as expert in crystallographyc techniques for the study of protein structures and protein-ligand interactions.

2009 - He became member of the Scientific Committee of the IC.

2010 - Responsible of the Bilateral Project CNR-JSPS between Italy and Japan (2010-2011), entitled "Study of potential drugs for the treatment of the metabolic syndrome: search of new PPAR ligands with enhanced therapeutic efficacy by structural biology techniques, NMR and microcalorimetry analysis".

2010 – He has been granted “Invited Professorship”

2010 - Responsible of the O.U. IC-CNR for the project of Cariplo Foundation entitled: 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" (2010-2012).

2010 - He gave three seminars on PPARs in the Universities of Tokyo, Osaka and Kyoto.

2010 - Responsible of the Commessa CNR "Cristallografia di biomolecole e studi funzionali" PM.P01.023

2011 – Responsible of the O.U. – IC CNR for the PRIN2009 project entitled: “Integrated multidisciplinary approaches to improve the discovery of novel nuclear receptor ligands: from virtual screening to in vivo evaluation of newly identified compounds”.

2012 – He gave a seminar on PPARs in the Showa Pharmaceutical University of Tokyo at the conclusion of the Bilateral Project CNR/JSPS.

 

 

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.

In collaboration with the University of Pavia, we developed new chromatographic tools based on the LBD of PPARgamma receptor for affinity screening of drug candidates (Frontal affinity chromatography or FAC interfaced to Mass Spectrometry).

 

 

Selected publications :

Selected publications (2000-2012):

 

1. A. Laghezza, G. Pochetti, A. Lavecchia, G. Fracchiolla, S. Faliti,L.Piemontese, C. Di Giovanni, V. Iacobazzi, V. Infantino, R. Montanari, D. Capelli, P. Tortorella,and F. Loiodice, “New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists able to upregulate the mitochondrial carnitine shuttle system gene expression”, J. Med. Chem., DOI: 10.1021/jm301018z.

 

2. L. Porcelli, F. Gilardi, A. Laghezza, L. Piemontese, N. Mitro, A.

Azzariti, F. Altieri, L. Cervoni, G. Fracchiolla, M. Giudici, U.Guerrini,

A. Lavecchia, R. Montanari, C. Di Giovanni, A. Paradiso, G. Pochetti, G.M.

Simone, P. Tortorella, M. Crestani and F. Loiodice, “Synthesis,

characterization and biological evaluation of ureidofibrate-like

derivatives endowed with peroxisome proliferator-activated receptor

activity”, J. Med. Chem., 55, 37-54, 2012.

 

3. G. FRACCHIOLLA, A. LAGHEZZA, L. PIEMONTESE, M. PARENTE, A. LAVECCHIA, G.

POCHETTI, R. MONTANARI, C. DI GIOVANNI, G. CARBONARA, P. TORTORELLA, E.

NOVELLINO, F. LOIODICE, “Synthesis, biological evaluation and molecular

investigation of fluorinated peroxisomes proliferator-activated receptors

a/g dual agonists”, Bioorganic & Medicinal Chemistry, 20, 2141-2151, 2012.

 

4. CALLERI E., FRACCHIOLLA G., MONTANARI R., POCHETTI G., LAVECCHIA A.,

LOIODICE F., LAGHEZZA A., PIEMONTESE L., MASSOLINI G., TEMPORINI C.

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, 2012.

 

5. LOIODICE F., POCHETTI G.

"Structural insight into the crucial role of ligand chirality in the

activation of PPARs by crystallographic methods". Current Topics in

Medicinal Chemistry, 11, 819-839, 2011.

 

6. 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 interaction analysis and site-directed mutagenesis". J. Med. Chem., 53, 4354-4366, 2010.

 

7. FRACCHIOLLA G., LAGHEZZA A., PIEMONTESE L., TORTORELLA P., MAZZA F.,

MONTANARI R., POCHETTI G., LAVECCHIA A., NOVELLINO E., PIERNO S., CONTE

CAMERINO D., LOIODICE F.

"New 2-Aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors dual agonists with improved potency and reduced adverse effects on skeletal muscle function"

J. Med. Chem., 52, 6382-6393, 2009.

 

8. POCHETTI G., MONTANARI R., GEGE C., CHEVRIER C., TAVERAS A.G., MAZZA F.

"Extra binding region induced by non-zinc chelating inhibitors into the S1’ subsite of matrix metalloproteinase8 (MMP-8)"

J. Med. Chem., 52, 1040-1049, 2009.

 

9. 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., 51, 7768-7776, 2008.

 

10. ASCHI M., BESKER N., RE NAZZARENO, POCHETTI G., COLETTI C., GALLINA

C., MAZZA F.

"Stereoselectivity by enantiomeric inhibitors of matrix metalloproteinase-8: new insights from molecular dynamics simulations"

J. Med. Chem., 50, 211-218, 2007.

 

11. 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., 282, 17314-17324, 2007.

 

12. CAMPESTRE C.,AGAMENNONE M., TORTORELLA P.,PREZIUSO S.,BIASONE A., GAVUZZO

E.,POCHETTI G., MAZZA F., HILLER O., TSCHESCHE H.,CONSALVI V.,GALLINA C.

"N-Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8"

Bioorg. & Med. Chem. Lett., 16, 20-24, 2006.

 

13. POCHETTI G., GAVUZZO E., CAMPESTRE C., AGAMENNONE M., TORTORELLA P.,

CONSALVI V., GALLINA C., HILLER O., TSCHESCHE H., TUCKER P.A.,MAZZA F.

"Structural insight into the stereoselctive inhibition of MMP-8 by enantiomeric sulfonamide phosphonates"

J. Med. Chem., 49, 923-931, 2006.

 

14. PERILLI M., ETTORRE D., SEGATORE B., CAPORALE B., DE SANTIS F.,

POCHETTI G., BRIGANTE G., MAZZA F., TAVIO M. M., AMICOSANTE G.

"Overexpression system and biochemical profile of CTX-M-3

extended-spectrum -lactamase expressed in Escherichia Coli"

FEMS Microbiology Letters, 241, 229-232, 2004.

 

15. ASCHI M., ROCCATANO D., DI NOLA A., GALLINA C., GAVUZZO E.,

POCHETTI G., PIEPER M., TSCHESCHE H., MAZZA F.

"Computational Study of the Catalytic Domain of Human

Neutrophil Collagenase. Specific Role of the S3 and S'3

Subsites in the Interaction with a Phosphonate Inhibitor"

Journal of Computer-Aided Molecular Design, 16, 213-225, 2002.

 

16. BACIOCCHI E., FABBRINI M., LANZALUNGA O., MANDUCHI L.,

POCHETTI G.

"Prochiral Selectivity in H2O2-Promoted Oxidation of

Arylalkanols Catalysed by Chloroperoxidase".

Eur. J. Biochem., 268, 665-672, 2001.

 

17. D'ALESSIO S., GALLINA C., GAVUZZO E., GIORDANO C.,

GORINI B., MAZZA F., PAGLIALUNGA PARADISI M., PANINI G.,

POCHETTI G.

"Conformationally Constrained Analogues of Endogenous

Tripeptide Inhibitors of Zinc Metalloproteinases".

Eur. J. Med. Chem., 36, 43-53, 2001.

 

18. GAVUZZO E., POCHETTI G., MAZZA F., GALLINA C., GORINI B.,

D'ALESSIO S., PIEPER M., TSCHESCHE H., TUCKER P.

"Two Crystal Structures of Human Neutrophil Collagenase,

One Complexed with a Primed- and the Other with an

Unprimed-Side Inhibitor: Implications for Drug Design".

J. Med. Chem., 43, 3377-3385 (2000).

 

 

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