Dr. Maurizio Pellecchia’s Lab: Studcure-based Drug Discovery

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Wednesday, 10 June 2009 11:37

Dr. Pellecchia’s research group at Burnham Institute for Medical Research focuses on the characterization of intermolecular interactions, on the determination of protein structures and on the development of small molecule inhibitors of protein targets involved in cell-signaling, virulence factors and host-pathogens interactions.

The resulting compounds are used as molecular probes to provide further understanding on the mechanism of action of their respective targets. The overall goal of the laboratory is to successfully bring together basic sciences involving modern nuclear magnetic resonance spectroscopy (NMR) techniques, computer modeling and traditional medicinal chemistry to elucidate the molecular basis of disease and to develop novel therapeutic compounds. Amongst the several projects that Dr. Pellecchia’s laboratory have initiated in the past years, noteworthy are the discovery, characterization and further development of potential therapeutic compounds targeting proteins of the Bcl-2 family, such as Bcl-xL and Bcl-2 (cancer targets) as well as Bid (involved in neurodegenerative diseases) and protein kinases such as p38 and Jnk (inflammation and diabetes). In addition, other very active areas of research involve the development of antitoxin compounds targeting the Anthrax metalloproteinase LF and protein components of the type-III secretion system, common to many pathogens, including Yersinia pestis and Salmonella. Finally, an area in which Dr. Pellecchia remains particularly interested is the development of novel NMR-based techniques to aid the characterization of protein structure, protein-protein and protein-ligand interactions using NMR spectroscopy. The design and synthesis of several high affinity ligands, for example, was made possible by the SAR by ILOEs approach, a NMR-based method developed in Dr. Pellecchia’s laboratory that enables the identification of high affinity ligands for a given protein target.

Recent Publications:

1: SNCA variants are associated with increased risk for multiple system atrophy.

Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wüllner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun MS, Poewe W, Wenning GK, Hardy JA, Singleton AB, Gasser T.

Ann Neurol. 2009 May;65(5):610-4.

PMID: 19475667 [PubMed - in process]

History or ecology? Substrate type as a major driver of patial genetic structure in Alpine plants.

Alvarez N, Thiel-Egenter C, Tribsch A, Holderegger R, Manel S, Schönswetter P, Taberlet P, Brodbeck S, Gaudeul M, Gielly L, Küpfer P, Mansion G, Negrini R, Paun O, Pellecchia M, Rioux D, Schüpfer F, Van Loo M, Winkler M, Gugerli F; IntraBioDiv Consortium.

Ecol Lett. 2009 Apr 22. [Epub ahead of print]

PMID: 19392716 [PubMed - as supplied by publisher]

Fragment-based drug discovery takes a virtual turn.

Pellecchia M.

Nat Chem Biol. 2009 May;5(5):274-5. No abstract available.

PMID: 19377449 [PubMed - indexed for MEDLINE]

Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins.

Wei J, Kitada S, Rega MF, Emdadi A, Yuan H, Cellitti J, Stebbins JL, Zhai D, Sun J, Yang L, Dahl R, Zhang Z, Wu B, Wang S, Reed TA, Lawrence N, Sebti S, Reed JC, Pellecchia M.

Mol Cancer Ther. 2009 Apr;8(4):904-13.

PMID: 19372563 [PubMed - indexed for MEDLINE]

RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease.

Lovicu M, Lepori MB, Incollu S, Dessì V, Zappu A, Iorio R, D'Ambrosi M, Pellecchia MT, Barone P, Maggiore G, De Virgiliis S, Cao A, Loudianos G.

Genet Test Mol Biomarkers. 2009 Apr;13(2):185-91.

PMID: 19371217 [PubMed - in process]

Structure-activity relationship studies of a novel series of anthrax lethal factor inhibitors.

Johnson SL, Chen LH, Barile E, Emdadi A, Sabet M, Yuan H, Wei J, Guiney D, Pellecchia M.

Bioorg Med Chem. 2009 May 1;17(9):3352-68. Epub 2009 Mar 26.

PMID: 19359184 [PubMed - in process]

Discovery and binding studies on a series of novel Pin1 ligands.

Wu B, Rega MF, Wei J, Yuan H, Dahl R, Zhang Z, Pellecchia M.

Chem Biol Drug Des. 2009 Apr;73(4):369-79.

PMID: 19291099 [PubMed - indexed for MEDLINE]

Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors.

De SK, Chen LH, Stebbins JL, Machleidt T, Riel-Mehan M, Dahl R, Chen V, Yuan H, Barile E, Emdadi A, Murphy R, Pellecchia M.

Bioorg Med Chem. 2009 Apr 1;17(7):2712-7. Epub 2009 Feb 26.

PMID: 19282190 [PubMed - in process]

Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.

De SK, Stebbins JL, Chen LH, Riel-Mehan M, Machleidt T, Dahl R, Yuan H, Emdadi A, Barile E, Chen V, Murphy R, Pellecchia M.

J Med Chem. 2009 Apr 9;52(7):1943-52.

PMID: 19271755 [PubMed - indexed for MEDLINE]

10:

BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma.

Gaitonde S, De SK, Tcherpakov M, Dewing A, Yuan H, Riel-Mehan M, Krajewski S, Robertson G, Pellecchia M, Ronai Z.

Pigment Cell Melanoma Res. 2009 Apr;22(2):187-95. Epub 2009 Jan 17.

PMID: 19175524 [PubMed - indexed for MEDLINE]

11:

Perspectives on NMR in drug discovery: a technique comes of age.

Pellecchia M, Bertini I, Cowburn D, Dalvit C, Giralt E, Jahnke W, James TL, Homans SW, Kessler H, Luchinat C, Meyer B, Oschkinat H, Peng J, Schwalbe H, Siegal G.

Nat Rev Drug Discov. 2008 Sep;7(9):738-45. Review.

PMID: 19172689 [PubMed - indexed for MEDLINE]

12:

Diffusion-weighted imaging in multiple system atrophy: a comparison between clinical subtypes.

Pellecchia MT, Barone P, Mollica C, Salvatore E, Ianniciello M, Longo K, Varrone A, Vicidomini C, Picillo M, De Michele G, Filla A, Salvatore M, Pappatà S.

Mov Disord. 2009 Apr 15;24(5):689-96.

PMID: 19117367 [PubMed - in process]

13:

Binding properties of the C-terminal domain of VIAF.

Bisson WH, Zhang Z, Welsh K, Huang JW, Ryan J, Reed JC, Pellecchia M.

Chem Biol Drug Des. 2008 Nov;72(5):331-6.

PMID: 19012568 [PubMed - indexed for MEDLINE]

14:

NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor.

Leone M, Cellitti J, Pellecchia M.

Biochemistry. 2008 Dec 2;47(48):12721-8.

PMID: 18991394 [PubMed - indexed for MEDLINE]

15:

Cerebellar and pyramidal dysfunctions, palpebral ptosis and weakness as presenting symptoms of PARK-2.

Amboni M, Pellecchia MT, Cozzolino A, Picillo M, Vitale C, Barone P, Varrone A, Garavaglia B, Gambelli S, Federico A.

Mov Disord. 2009 Jan 30;24(2):303-5. No abstract available.

PMID: 18973255 [PubMed - indexed for MEDLINE]

16:

Fragment-based design of small molecule X-linked inhibitor of apoptosis protein inhibitors.

Huang JW, Zhang Z, Wu B, Cellitti JF, Zhang X, Dahl R, Shiau CW, Welsh K, Emdadi A, Stebbins JL, Reed JC, Pellecchia M.

J Med Chem. 2008 Nov 27;51(22):7111-8.

PMID: 18956862 [PubMed - indexed for MEDLINE]

17:

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site.

Stebbins JL, De SK, Machleidt T, Becattini B, Vazquez J, Kuntzen C, Chen LH, Cellitti JF, Riel-Mehan M, Emdadi A, Solinas G, Karin M, Pellecchia M.

Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16809-13. Epub 2008 Oct 15.

PMID: 18922779 [PubMed - indexed for MEDLINE]

18:

Synthesis and evaluation of Apogossypol atropisomers as potential Bcl-xL antagonists.

Wei J, Rega MF, Kitada S, Yuan H, Zhai D, Risbood P, Seltzman HH, Twine CE, Reed JC, Pellecchia M.

Cancer Lett. 2009 Jan 8;273(1):107-13. Epub 2008 Sep 7.

PMID: 18782651 [PubMed - indexed for MEDLINE]

19:

Perspectives on NMR in drug discovery: a technique comes of age.

Pellecchia M, Bertini I, Cowburn D, Dalvit C, Giralt E, Jahnke W, James TL, Homans SW, Kessler H, Luchinat C, Meyer B, Oschkinat H, Peng J, Schwalbe H, Siegal G.

Nat Rev Drug Discov. 2008 Aug 26. [Epub ahead of print]

PMID: 18725883 [PubMed - as supplied by publisher]

20:

Subclinical sensory abnormalities in unaffected PINK1 heterozygotes.

Fiorio M, Valente EM, Gambarin M, Bentivoglio AR, Ialongo T, Albanese A, Barone P, Pellecchia MT, Brancati F, Moretto G, Fiaschi A, Tinazzi M.

J Neurol. 2008 Sep;255(9):1372-7. Epub 2008 Jul 3.

PMID: 18584234 [PubMed - indexed for MEDLINE]

21:

Bid-induced release of AIF from mitochondria causes immediate neuronal cell death.

Landshamer S, Hoehn M, Barth N, Duvezin-Caubet S, Schwake G, Tobaben S, Kazhdan I, Becattini B, Zahler S, Vollmar A, Pellecchia M, Reichert A, Plesnila N, Wagner E, Culmsee C.

Cell Death Differ. 2008 Oct;15(10):1553-63. Epub 2008 Jun 6.

PMID: 18535584 [PubMed - indexed for MEDLINE]

22:

Development of paramagnetic probes for molecular recognition studies in protein kinases.

Vazquez J, De SK, Chen LH, Riel-Mehan M, Emdadi A, Cellitti J, Stebbins JL, Rega MF, Pellecchia M.

J Med Chem. 2008 Jun 26;51(12):3460-5.

PMID: 18494454 [PubMed - indexed for MEDLINE]

23:

Red flags for multiple system atrophy.

Köllensperger M, Geser F, Seppi K, Stampfer-Kountchev M, Sawires M, Scherfler C, Boesch S, Mueller J, Koukouni V, Quinn N, Pellecchia MT, Barone P, Schimke N, Dodel R, Oertel W, Dupont E, Østergaard K, Daniels C, Deuschl G, Gurevich T, Giladi N, Coelho M, Sampaio C, Nilsson C, Widner H, Sorbo FD, Albanese A, Cardozo A, Tolosa E, Abele M, Klockgether T, Kamm C, Gasser T, Djaldetti R, Colosimo C, Meco G, Schrag A, Poewe W, Wenning GK; European MSA Study Group.

Mov Disord. 2008 Jun 15;23(8):1093-9.

PMID: 18442131 [PubMed - indexed for MEDLINE]

24:

PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum.

Marongiu R, Ferraris A, Ialongo T, Michiorri S, Soleti F, Ferrari F, Elia AE, Ghezzi D, Albanese A, Altavista MC, Antonini A, Barone P, Brusa L, Cortelli P, Martinelli P, Pellecchia MT, Pezzoli G, Scaglione C, Stanzione P, Tinazzi M, Zecchinelli A, Zeviani M, Cassetta E, Garavaglia B, Dallapiccola B, Bentivoglio AR, Valente EM; Italian PD Study Group.

Hum Mutat. 2008 Apr;29(4):565.

PMID: 18330912 [PubMed - indexed for MEDLINE]

25:

Mitochondrial genomes of extinct aurochs survive in domestic cattle.

Achilli A, Olivieri A, Pellecchia M, Uboldi C, Colli L, Al-Zahery N, Accetturo M, Pala M, Kashani BH, Perego UA, Battaglia V, Fornarino S, Kalamati J, Houshmand M, Negrini R, Semino O, Richards M, Macaulay V, Ferretti L, Bandelt HJ, Ajmone-Marsan P, Torroni A.

Curr Biol. 2008 Feb 26;18(4):R157-8. No abstract available.

PMID: 18302915 [PubMed - indexed for MEDLINE]

26:

Comparison between a dual-head and a brain-dedicated SPECT system in the measurement of the loss of dopamine transporters with [123I]FP-CIT.

Varrone A, Sansone V, Pellecchia MT, Amboni M, Salvatore E, De Michele G, Filla A, Barone P, Pappatà S, Salvatore M.

Eur J Nucl Med Mol Imaging. 2008 Jul;35(7):1343-9. Epub 2008 Feb 19.

PMID: 18283454 [PubMed - indexed for MEDLINE]

27:

Rhodanine derivatives as selective protease inhibitors against bacterial toxins.

Johnson SL, Chen LH, Harbach R, Sabet M, Savinov A, Cotton NJ, Strongin A, Guiney D, Pellecchia M.

Chem Biol Drug Des. 2008 Feb;71(2):131-9. Epub 2008 Jan 19.

PMID: 18221310 [PubMed - indexed for MEDLINE]

28:

Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048).

Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M, Reed JC.

Blood. 2008 Mar 15;111(6):3211-9. Epub 2008 Jan 17.

PMID: 18202226 [PubMed - indexed for MEDLINE]

29:

The arginine growth hormone stimulation test in bradykinetic-rigid parkinsonisms.

Pellecchia MT, Longo K, Manfredi M, Lucetti C, Cossu G, Petrone A, Marconi R, Sensi M, Epifanio A, Eleopra R, Marchese R, Scaravilli T, Morgante L, Abbruzzese G, Bonuccelli U, Donati E, Pivonello R, Colao A, Barone P.

Mov Disord. 2008 Jan 30;23(2):190-4.

PMID: 18044703 [PubMed - indexed for MEDLINE]

30:

Nuclear magnetic resonance fragment-based identification of novel FKBP12 inhibitors.

Stebbins JL, Zhang Z, Chen J, Wu B, Emdadi A, Williams ME, Cashman J, Pellecchia M.

J Med Chem. 2007 Dec 27;50(26):6607-17. Epub 2007 Nov 27.

PMID: 18038971 [PubMed - indexed for MEDLINE]

31:

Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin.

Lepori MB, Lovicu M, Dessi V, Zappu A, Incollu S, Zancan L, Giacchino R, Iorio R, Vajro P, Maggiore G, Marcellini M, Barbera C, Pellecchia MT, Simonetti R, Kostic V, Farci AM, Solinas A, De Virgiliis S, Cao A, Loudianos G.

Genet Test. 2007 Fall;11(3):328-32.

PMID: 17949296 [PubMed - indexed for MEDLINE]

32:

The PTB domain of tensin: NMR solution structure and phosphoinositides binding studies.

Leone M, Yu EC, Liddington RC, Pasquale EB, Pellecchia M.

Biopolymers. 2008 Jan;89(1):86-92.

PMID: 17922498 [PubMed - indexed for MEDLINE]

33:

Luminescent silica nanobeads: characterization and evaluation as efficient cytoplasmatic transporters for T-lymphocytes.

Bottini M, Cerignoli F, Mills DM, D'Annibale F, Leone M, Rosato N, Magrini A, Pellecchia M, Bergamaschi A, Mustelin T.

J Am Chem Soc. 2007 Jun 27;129(25):7814-23. Epub 2007 Jun 2.

PMID: 17542582 [PubMed - indexed for MEDLINE]

34:

Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens.

Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, Bottini M, Rega MF, Parent A, Desjardins R, Fugere M, Day R, Sabet M, Pellecchia M, Liddington RC, Smith JW, Mustelin T, Guiney DG, Lebl M, Strongin AY.

J Biol Chem. 2007 Jul 20;282(29):20847-53. Epub 2007 May 30.

PMID: 17537721 [PubMed - indexed for MEDLINE]

35:

Structure-based discovery of a new class of Bcl-xL antagonists.

Rega MF, Leone M, Jung D, Cotton NJ, Stebbins JL, Pellecchia M.

Bioorg Chem. 2007 Aug;35(4):344-53. Epub 2007 May 21.

PMID: 17512966 [PubMed - indexed for MEDLINE]

36:

A fragment-based approach for the discovery of isoform-specific p38alpha inhibitors.

Chen J, Zhang Z, Stebbins JL, Zhang X, Hoffman R, Moore A, Pellecchia M.

ACS Chem Biol. 2007 May 22;2(5):329-36. Epub 2007 Apr 27.

PMID: 17465519 [PubMed - indexed for MEDLINE]