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Proteomics and Systems Biology: Application in Drug Discovery and Development

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Systems Biology in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 662))

Abstract

Studies of complex biological systems aimed at understanding their functions at a global level are the goals of systems biology. Proteomics, generally regarded as the comprehensive study of the expression of all the proteins at a particular time in different organs, tissues, and cell types is a key enabling technology for the systems biology approach. Rapid advances in this regard have been made following the success of the human genome project as well as those of various animals and microorganisms. Possibly, one of the most promising outcomes from studies on the human genome and proteome is the identification of potential new drugs for the treatment of different diseases and tailoring the drugs for individualized patient therapy. Following the identification of a new drug candidate, knowledge on organ and system-level responses helps prioritize the drug targets and design clinical trials based on their efficacy and safety. Toxicoproteomics is playing an important role in that respect. In essence, over the past decade, proteomics has played a major role in drug discovery and development. In this review article, we explain systems biology, discuss the current proteomic technologies, and highlight some important applications of proteomics and systems biology approaches in drug discovery and development.

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References

  1. Weston AD, Hood L (2004) Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J Proteome Res 3:179–196

    Article  CAS  PubMed  Google Scholar 

  2. Heller MJ (2002) DNA microarray technology: devices, systems, and applications. Annu Rev Biomed Eng 4:129–153

    Article  CAS  PubMed  Google Scholar 

  3. Griffin TJ, Gygi SP, Ideker T, Rist B, Eng J, Hood L, Aebersold R (2002) Complementary profiling of gene expression at the transcriptome and proteome levels in Saccharomyces cerevisiae. Mol Cell Proteomics 1:323–333

    Article  CAS  PubMed  Google Scholar 

  4. Szkanderová S, Port M, Stulík J, Hernychová L, Kasalová I, Van Beuningen D, Abend M (2003) Comparison of the abundance of 10 radiation-induced proteins with their differential gene expression in L929 cells. Int J Radiat Biol 79:623–633

    Article  PubMed  Google Scholar 

  5. Greenbaum D, Colangelo C, Williams K, Gerstein M (2003) Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 4:117

    Article  PubMed  PubMed Central  Google Scholar 

  6. Anderson NL, Anderson NG (2002) The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1:845–67, Erratum in: Mol Cell Proteomics. 2, 50

    Article  CAS  PubMed  Google Scholar 

  7. Wilkins MR, Pasquali C, Appel RD, Ou K, Jean-Charles Sanchez OG, Yan JX, Gooley AA, Hughes G, Humphery-Smith I, Williams KL, Hochstrasser DF (1996) From proteins to proteomes: large scale protein identification by two-dimensional electrophoresis and amino acid analysis. Nat Biotechnol 14:61–65

    Article  CAS  Google Scholar 

  8. Chakravarti DN, Chakravarti B, Moutsatsos I (2002) Informatic tools for proteome profiling. BioTechniques Suppl:4–10, 12–5

    Google Scholar 

  9. Margolis J, Kenrick KG (1969) 2 dimensional resolution of plasma proteins by combination of polyacrylamide disc and gradient gel electrophoresis. Nature 221:1056–1057

    Article  CAS  PubMed  Google Scholar 

  10. O’Farrell PH (1975) High resolution two dimensional electrophoresis of proteins. J Biol Chem 250:4007–4021

    PubMed  PubMed Central  Google Scholar 

  11. Klose J (1975) Protein mapping by combined isoelectric focusing electrophoresis of mouse tissues. A novel approach to testing for induced point mutations in mammals. Humangenetik 26:231–243

    CAS  PubMed  Google Scholar 

  12. Unlu M, Morgan ME, Minden JS (1997) Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis 18:2071–2077

    Article  CAS  PubMed  Google Scholar 

  13. Chakravarti DN, Gallagher S, Chakravarti B (2004) Difference gel electrophoresis: application in quantitative proteomics research. Curr Proteomics 1:261–271

    Article  CAS  Google Scholar 

  14. Tonge R, Shaw J, Middleton B, Rowlinson R, Rayner S, Young J, Pognan F, Hawkins E, Currie I, Davison M (2001) Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics 1:117–124

    Article  Google Scholar 

  15. Han X, Aslanian A, Yates JR (2008) Mass spectrometry for proteomics. Curr Opin Chem Biol 12:483–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guerrera IC, Kleiner O (2005) Analysis of mass spectrometry in proteomics. Biosci Rep 25:71–93

    Article  CAS  PubMed  Google Scholar 

  17. Domon B, Alving K, He T, Ryan TE, Patterson SD (2002) Enabling parallel protein analysis through mass spectrometry. Curr Opin Mol Ther 4:577–586

    CAS  PubMed  Google Scholar 

  18. Yates JR (2004) Mass spectral analysis in proteomics. Annu Rev Biophys Biomol Struct 312:212–217

    Google Scholar 

  19. Domon B, Aebersold R (2006) Mass spectrometry and protein analysis. Science 31:212–217

    Article  Google Scholar 

  20. Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM (1989) Electrospray ionization for mass spectrometry of large biomolecules. Science 246:64–71

    Article  CAS  PubMed  Google Scholar 

  21. Karas M, Hillenkamp F (1988) Laser desorption ionization of proteins with molecular masses exceeding 10,000 daltons. Anal Chem 60:2299–2301

    Article  CAS  PubMed  Google Scholar 

  22. Zubarev RA, Kelleher NL, McLafferty FW (1998) Electron capture dissociation of multiply charged protein cations. A nonergodic process. J Am Chem Soc 120:3265–3266

    Article  CAS  Google Scholar 

  23. Zubarev R (2006) Protein primary structure using orthogonal fragmentation techniques in Fourier transform mass spectrometry. Expert Rev Proteomics 3:251–261

    Article  CAS  PubMed  Google Scholar 

  24. Syka JEP, Coon JJ, Schroeder MJ, Shabanowitz J, Hunt DF (2004) Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry. Proc Natl Acad Sci USA 101:9528–9533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pitteri SJ, Chrisman PA, Hogan JM, McLuckey SA (2005) Electron transfer ion/ion reactions in a three-dimensional quadrupole ion trap: reactions of doubly and triply protonated peptides with SO −2 . Anal Chem 77:1831–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R (1999) Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 17:994–999

    Article  CAS  PubMed  Google Scholar 

  27. Goodlett DR, Keller A, Watts JD, Newitt R, Yi EC, Purvine S, Eng JK, von Haller P, Peters EC, Horn DM, Tully DC, Brock A (2001) A novel multifunctional labeling reagent for enhanced protein characterization with mass spectrometry. Rapid Commun Mass Spectrom 15:2387–2392

    Article  Google Scholar 

  28. Peters EC, Horn DM, Tully DC, Brock A (2001) A novel multifunctional labeling reagent for enhanced protein characterization with mass spectrometry. Rapid Commun Mass Spectrom 15:2387–2392

    Article  CAS  PubMed  Google Scholar 

  29. Munchbach M, Quadroni M, Miotto G, James P (2000) Quantitation and facilitated de novo sequencing of proteins by isotopic N-terminal labeling of peptides with a fragmentation-directing moiety. Anal Chem 72:4047–4057

    Article  CAS  PubMed  Google Scholar 

  30. Oda Y, Huang K, Cross FR, Cowburn D, Chait BT (1999) Accurate quantitation of protein expression and site-specific phosphorylation. Proc Natl Acad Sci USA 96:6591–6596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou H, Watts JD, Aebersold R (2001) A systematic approach to the analysis of protein phosphorylation. Nat Biotechnol 19:375–378

    Article  CAS  PubMed  Google Scholar 

  32. Goshe MB, Conrads TP, Panisko EA, Angell NH, Veenstra TD, Smith RD (2001) Phosphoprotein isotope-coded affinity tag approach for isolating and quantitating phosphopeptides in proteome-wide analyses. Anal Chem 73:2578–2586

    Article  CAS  PubMed  Google Scholar 

  33. Goshe MB, Veenstra TD, Panisko EA, Conrads TP, Angell NH, Smith RD (2002) Phosphoprotein isotope-coded affinity tags: application to the enrichment and identification of low-abundance phosphoproteins. Anal Chem 74:607–616

    Article  CAS  PubMed  Google Scholar 

  34. Ficarro SB, McCleland ML, Stukenberg PT, Burke DJ, Ross MM, Shabanowitz J, Hunt DF, White FM (2002) Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae. Nat Biotechnol 20:301–305

    Article  CAS  PubMed  Google Scholar 

  35. Cohen P (2001) The role of protein phosphorylation in human health and disease. The Sir Hans Krebs Medal Lecture. Eur J Biochem 268:5001–5010

    Article  CAS  PubMed  Google Scholar 

  36. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127:635–648

    Article  CAS  PubMed  Google Scholar 

  37. Nita-Lazar A, Saito-Benz H, White FM (2008) Quantitative phosphoproteomics by mass spectrometry: past, present, and future. Proteomics 8:4433–4443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu Li-R, Issaq HJ, Veenstra TD (2007) Phosphoproteomics for the discovery of kinases as cancer biomarkers and drug targets. Proteomics Clin Appl 1:1042–1057

    Article  CAS  PubMed  Google Scholar 

  39. Mirzaei H, Mcbee JK, Watts J, Aebersold R (2007) Comparative evaluation of current peptide production platforms used in absolute quantification in proteomics. Mol Cell Proteomics 7:813–823

    Article  PubMed  Google Scholar 

  40. Wilson DS, Nock S (2003) Recent developments in protein microarray technology. Angew Chem Int Ed Engl 42:494–500

    Article  CAS  PubMed  Google Scholar 

  41. Calvert VS, Tang Y, Boveia V, Wulfkuhle J, Schutz-Geschwender A, Olive DM, Liotta LA, Petricoin EF (2004) Development of multiplexed protein profiling and detection using near infrared detection of reverse phase protein microarrays. Clin Proteomics J 1:81–89

    Article  CAS  Google Scholar 

  42. Geho DH, Lahar N, Ferrari M, Petricoin EF, Liotta LA (2004) Opportunities for nanotechnology-based innovation in tissue proteomics. Biomed Microdevices 6:2319

    Article  Google Scholar 

  43. Zhu H, Bilgin M, Bangham R, Hall D, Casamayor A, Bertone P, Lan N, Jansen R, Bidlingmaier S, Houfek T, Mitchell T, Miller P, Dean RA, Gerstein M, Snyder M (2001) Global analysis of protein activities using proteome chips. Science 293:2101–2105

    Article  CAS  PubMed  Google Scholar 

  44. Espina V, Wulfkuhle JD, Calvert VS, VanMeter A, Zhou W, Coukos G, Geho DH, Petricoin EF, Liotta LA (2006) Laser capture microdissection. Nat Protoc 1:586–603

    Article  CAS  PubMed  Google Scholar 

  45. Grubb RL, Calvert VS, Wulfkuhle JD, Paweletz CP, Linehan WM, Phillips JL, Chuaqui R, Valasco A, Gillespie J, Emmert-Buck M, Liotta LA, Petricoin EF (2003) Signal pathway profiling of prostate cancer using reverse phase protein microarrays. Proteomics 3:2142–2146

    Article  CAS  PubMed  Google Scholar 

  46. Tolcher AW, Reyno L, Venner PM, Ernst SD, Moore M, Geary RS, Chi K, Hall S, Walsh W, Dorr A, Eisenhauer E (2002) A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 inpatients with hormone-refractory prostate cancer. Clin Cancer Res 8:2530–2535

    CAS  PubMed  Google Scholar 

  47. Paweletz CP, Charboneau L, Bichsel VE, Simone NL, Chen T, Gillespie JW, Emmert-Buck MR, Roth MJ, Petricoin EF III, Liotta LA (2001) Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 20:1981–1989

    Article  CAS  PubMed  Google Scholar 

  48. Wulfkuhle JD, Aquino JA, Calvert VS, Fishman DA, Coukos G, Liotta LA, Petricoin EF (2003) Signal pathway profiling of ovarian cancer from human tissue specimens using reverse-phase protein microarrays. Proteomics 3:2085–2090

    Article  CAS  PubMed  Google Scholar 

  49. Zha H, Raffeld M, Charboneau L, Pittaluga S, Kwak LW, Petricoin E III, Liotta LA, Jaffe ES (2004) Similarities of prosurvival signals in Bcl-2-positive and Bcl-2-negative follicular lymphomas identified by reverse phase protein microarray. Lab Invest 84:235–244

    Article  CAS  PubMed  Google Scholar 

  50. Sheehan KM, Calvert VS, Kay EW, Lu Y, Fishman D, Espina V, Aquino J, Speer R, Araujo R, Mills GB, Liotta LA, Petricoin EF, Wulfkuhle JD (2005) Use of reverse phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma. Mol Cell Proteomics 4:346–355

    Article  CAS  PubMed  Google Scholar 

  51. Hanash S (2003) Disease proteomics. Nature 422:226–232

    Article  CAS  PubMed  Google Scholar 

  52. Tyers M, Mann M (2003) From genomics to proteomics. Nature 422:193–197

    Article  CAS  PubMed  Google Scholar 

  53. Agaton C, Galli J, Hoiden Guthenberg I, Janzon L, Hansson M, Asplund A, Brundell E, Lindberg S, Ruthberg I, Wester K, Wurtz D, Hoog C, Lundeberg J, Stahl S, Ponten F, Uhlen M (2003) Affinity proteomics for systematic protein profiling of chromosome 21 gene products in human tissues. Mol Cell Proteomics 2:405–414

    CAS  PubMed  Google Scholar 

  54. Haab BB, Paulovich AG, Anderson NL, Clark AM, Downing GJ, Hermjakob H, Labaer J, Uhlen M (2006) A reagent resource to identify proteins and peptides of interest for the cancer community: a workshop report. Mol Cell Proteomics 5:1996–2007

    Article  CAS  PubMed  Google Scholar 

  55. Vorderwulbecke S, Cleverly S, Weinberger SR, Wiesner A (2005) Protein quantification by SELDI-TOF-MS based ProteinChip® system. Nat Methods 2:393–395

    Article  Google Scholar 

  56. Wiesner A (2004) Detection of tumor markers with ProteinChip technology. Curr Pharm Biotechnol 5:45–67

    Article  CAS  PubMed  Google Scholar 

  57. Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S (2002) Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biol Chem 277:12053–12060

    Article  CAS  PubMed  Google Scholar 

  58. Boyle MDP, Romer TG, Meeker AK, Sledjeski DD (2001) Use of surface-enhanced laser desorption ionization protein chip system to analyze streptococcal exotoxin B activity secreted by Streptococcus pyogenes. J Microbiol Methods 46:87–97

    Article  CAS  PubMed  Google Scholar 

  59. Weinberger SR, Boschetti E, Santambien P, Brenac V (2002) Surface-enhanced laser desorption-ionization retentate chromatography mass spectrometry (SELDI-RC-MS): a new method for rapid development of process chromatography conditions. J Chromatogr B Analyt Technol Biomed Life Sci 782:307–316

    Article  CAS  PubMed  Google Scholar 

  60. Grunhage F, Fischer HP, Dauerbruch T, Reichel C (2003) Drug- and toxin-induced hepatotoxicity. Z Gastroenterol 41:565–578

    Article  CAS  PubMed  Google Scholar 

  61. Rej R (1989) Aminotransferases in disease. Clin Lab Med 9:667–687

    CAS  PubMed  Google Scholar 

  62. Anderson NL, Taylor J, Hofmann JP, Esquer-Blasco R, Swift S, Anderson NG (1996) Simultaneous measurement of hundreds of liver proteins: application in assessment of liver function. Toxicol Pathol 24:72–76

    Article  CAS  PubMed  Google Scholar 

  63. Cunningham ML, Pippin LL, Anderson NL, Wenk ML (1995) The hepatocarcinogen methapyrilene but not the analog pyrilamine induces sustained hepatocellular replication and protein alterations in F344 rats in a 13-week feed study. Toxicol Appl Pharmacol 131:216–223

    Article  CAS  PubMed  Google Scholar 

  64. Arce A, Aicher L, Wahl D, Anderson NL, Meheus L, Raymackers J, Cordier A, Steiner S (1998) Changes in the liver protein pattern of female Wistar rats treated with the hypoglycemic agent SDZ PGU 693. Life Sci 63:2243–2250

    Article  CAS  PubMed  Google Scholar 

  65. Meneses-Lorente G, Guest PC, Lawrence J, Muniappa N, Knowles MR, Skynner HA, Salim K, Cristea I, Mortishire-Smith R, Gaskell SJ, Watt A (2004) A proteomic investigation of drug-induced steatosis in rat liver. Chem Res Toxicol 17:605–612

    Article  CAS  PubMed  Google Scholar 

  66. Meneses-Lorente G, Watt A, Salim K, Gaskell SJ, Muniappa N, Lawrence J, Guest PC (2006) Identification of early proteomic markers for hepatic steatosis. Chem Res Toxicol 19:986–998

    Article  CAS  PubMed  Google Scholar 

  67. Gao J, Ann Garulacan L, Storm SM, Hefta SA, Opiteck GJ, Lin JH, Moulin F, Dambach DM (2004) Identification of in vitro protein biomarkers of idiosyncratic liver toxicity. Toxicol In Vitro 18:533–541

    Article  CAS  PubMed  Google Scholar 

  68. Goodsaid FM (2004) Identification and measurement of genomic biomarkers of nephrotoxicity. J Pharmacol Toxicol Methods 49:183–186

    Article  CAS  PubMed  Google Scholar 

  69. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244

    Article  CAS  PubMed  Google Scholar 

  70. Bandara LR, Kelly MD, Lock EA, Kennedy S (2003) A correlation between a proteomic evaluation and conventional measurements in the assessment of renal proximal tubular toxicity. Toxicol Sci 73:195–206

    Article  CAS  PubMed  Google Scholar 

  71. Steiner S, Aicher L, Raymackers J, Meheus L, Esquer-Blasco R, Anderson NL, Cordier A (1996) Cyclosporine A decreases the protein level of the calcium-binding protein calbindin-D 28kDa in rat kidney. Biochem Pharmacol 51:253–258

    Article  CAS  PubMed  Google Scholar 

  72. Aicher L, Wahl D, Arce A, Grenet O, Steiner S (1998) New insights into cyclosporine A nephrotoxicity by proteome analysis. Electrophoresis 19:1998–2003

    Article  CAS  PubMed  Google Scholar 

  73. Gupta N, Law A, Poddar R, Louie M, Ray A, Chakravarti DN (2005) Toxicoproteomics: applications in drug development. Curr Proteomics 2:97–101

    Article  CAS  Google Scholar 

  74. Amacher DE (2010) The discovery and development of proteomic safety biomarkers for the detection of drug induced liver toxicity. Toxicol Appl Pharmacol 245:134–142

    Article  CAS  PubMed  Google Scholar 

  75. George J, Singh R, Mahmood Z, Shukla Y (2010) Toxicoproteomics: new paradigms in toxicology research. Toxicol Mech Methods [Epub ahead of print]

    Google Scholar 

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Acknowledgments

The authors would like to acknowledge the generous support provided by the Keck Graduate Institute of Applied Life Sciences, Claremont, CA, The Arnold and Mabel Beckman Foundation, the Ralph M. Parsons Foundation, and the National Science Foundation grant FIBR 0527023.

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Correspondence to Bulbul Chakravarti .

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Chakravarti, B., Mallik, B., Chakravarti, D.N. (2010). Proteomics and Systems Biology: Application in Drug Discovery and Development. In: Yan, Q. (eds) Systems Biology in Drug Discovery and Development. Methods in Molecular Biology, vol 662. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-800-3_1

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  • DOI: https://doi.org/10.1007/978-1-60761-800-3_1

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