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Combinatorial Methods to Engineer Small Molecules for Functional Genomics

  • Conference paper
The Role of Natural Products in Drug Discovery

Part of the book series: Ernst Schering Research Foundation Workshop ((SCHERING FOUND,volume 32))

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Abstract

The complete sequencing of the human genome will result in the identification of a huge number of coded proteins. However, in order for this information to be useful, the biological function of the coded proteins must be determined. Combinatorial small-molecule libraries will play a critical role in elucidating the function of these proteins. Combinatorial libraries can be used to rapidly assess the natural substrate specificity of newly identified enzymes. In addition, small-molecule libraries can be used to identify cell-permeable ligands that selectively activate or inactivate a protein target and therefore serve as powerful tools for understanding the function of the protein in cells and in animals.

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References

  • Attanasi OA, Filippone P (1997) Working twenty years on conjugated azo-alkenes (and environs) to find new entries in organic synthesis. Synlett 1128–1140

    Google Scholar 

  • Backes BJ, Ellman JA (1999) An alkanesulfonamide “safety-catch” linker for solid-phase synthesis. J Org Chem 64:2322–2330

    Article  CAS  Google Scholar 

  • Backes BJ, Virgilio AA, Ellman JA (1996) Activation method to prepare a highly reactive acylsulfonamide safety-catch linker for solid-phase synthesis. J Am Chem Soc 118:3055–3056

    Article  CAS  Google Scholar 

  • Backes BJ, Harris JL, Leonetti F, Ellman JA, Craik C (1999) Strategy to prepare positional-scanning libraries of fluorogenic peptide substrates that incorporate diverse PI substituents: facile and accurate specificity determination of thrombin and plasmin. Nature Biotech 18:187–193

    Article  Google Scholar 

  • Bastos M, Maeji NJ, Abeles RH (1995) Inhibitors of human heart chymase based on a peptide library. Proc Natl Acad Sei USA 92:6738–6742

    Article  CAS  Google Scholar 

  • Bednarski E, Lynch G (1996) Cytosolic proteolysis of tau by cathepsin D in hippocampus following suppression of cathepsins B and L. J Neurochem 67:1846–1855

    Article  PubMed  CAS  Google Scholar 

  • Bednarski E, Ribak CE, Lynch G (1997) Suppression of cathepsins B and L causes a proliferation of lysosomes and the formation of meganeurites in hippocampus. J Neurosci 17:4006–4021

    PubMed  CAS  Google Scholar 

  • Berman J, Green M, Sugg E, Andergegg R (1992) Rapid optimization of enzyme substrates using defined substrate mixtures. J Biol Chem 267:1434–1437

    PubMed  CAS  Google Scholar 

  • Bevan A, Brenner C, Fuller RS (1993) Quantitative assessment of enzyme specificity in vivo: P2 recognition by Kex2 protease defined in a genetic system. Proc Natl Acad Sei USA 95:10384–10389

    Article  Google Scholar 

  • Bi X, Lin B, Haque T, Lee CE, Skillman AG, Kuntz ID, Ellman JA, Lynch G (1999a) Novel cathepsin D inhibitors block the formation of hyperphospho-rylated tau fragments in hippocampus. J Neurochem 74:1469–1477

    Article  Google Scholar 

  • Bi X, Zhou J, Lynch G (1999b) Lysosomal protease inhibitors induce meganeurites and tangle-like structures in entorhinohippo-campal regions vulnerable to Alzheimer’s disease. Exp Neurol 158:312–327

    Article  PubMed  CAS  Google Scholar 

  • Birkett AJ, Yelamos B, Rodriguez-Crespo I, Gavilanes F, Peterson DL (1991) Determination of enzyme specificity in a complex mixture of peptide substrates by N-terminal sequence analysis. Anal Biochem 196:137–143

    Article  PubMed  CAS  Google Scholar 

  • Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, Kurdyla JT, McNulty DE, Drake FH, Gowen M, Levy MA (1996) Proteolytic activity of human osteoclast cathepsin K — expression, purification, activation, and substrate identification. J Biol Chem 271:12517–12524

    Article  PubMed  CAS  Google Scholar 

  • Campbell DA, Bermak JC, Burkoth TS, Patel DV (1995) A transition state analogue inhibitor combinatorial library. J Am Chem Soc 117:6738–6742

    Google Scholar 

  • Goldberg DE (1993) Hemoglobin degradation in Plasmodium-infected red blood cells. Semin Cell Biol 4:355–361

    Article  PubMed  CAS  Google Scholar 

  • Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJA, Goldberg DE, Kuntz ID, Ellman JA (1999) Single digit nanomolar, low molecular weight non-peptide inhibitors of malarial aspartyl protease plasmep-sin II. J Med Chem 42:1428–1440

    Article  PubMed  CAS  Google Scholar 

  • St Hilaire PM, Willert M, Juliano MA, Juliano L, Meldal M (1999) Fluorescence-quenched solid phase combinatorial libraries in the characterization of cysteine protease substrate specificity. J Comb Chem 1:509–523

    Article  Google Scholar 

  • Kick EK, Ellman JA (1995) Expedient method for the solid-phase synthesis of aspartic acid protease inhibitors directed toward the generation of libraries. J Med Chem 38:1427–1430

    Article  PubMed  CAS  Google Scholar 

  • Kick EK, Roe DC, Skillman AG, Liu G, Ewing TJA, Sun Y, Kuntz ID, Ellman JA (1997) Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D. Chem Biol 4:297–309

    Article  PubMed  CAS  Google Scholar 

  • Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ (1997) Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278:294–298

    Article  PubMed  CAS  Google Scholar 

  • Lam KS, Lebl M (1998) Synthesis of a one-bead one-compound combinatorial peptide library. Methods Mol Biol 87:1–6

    PubMed  CAS  Google Scholar 

  • Lee A, Huang L, Ellman JA (1999) General solid-phase method for the preparation of mechanism-based cysteine protease inhibitors. J Am Chem Soc 121:9907–9914 (available on the web: ASAP)

    Article  CAS  Google Scholar 

  • Lee CE, Kick EK, Ellman JA (1998) General solid-phase synthesis approach to prepare mechanism-based aspartyl protease inhibitor libraries. Identification of potent cathepsin D inhibitors. J Am Chem Soc 120:9735–9748

    Article  CAS  Google Scholar 

  • Lottenberg R, Hall JA, Blinder M, Binder EP, Jackson CM (1983) The action of thrombin on peptide p-nitroanilide substrates. Substrate selectivity and examination of hydrolysis under different reaction conditions. Biochim Biophys Acta 742:539–557

    Article  PubMed  CAS  Google Scholar 

  • Love S, Bridges LR, Case CP (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118:119–129

    Article  PubMed  Google Scholar 

  • Luker KE, Francis SE, Gluzman IY, Goldberg DE (1996) Kinetic analysis of plasmepsins I and II, aspartic proteases of the Plasmodium falciparum digestive vacuole. Mol Biochem Parasitol 79:71–78

    Article  PubMed  CAS  Google Scholar 

  • Matsuo ES, Shin RW, Billingsley ML, Vandevoorde A et al (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13:989–1002

    Article  PubMed  CAS  Google Scholar 

  • Matthews DJ, Wells JA (1993) Substrate phage: selection of protease substrates by monovalent phage display. Science 260:1113–1117

    Article  PubMed  CAS  Google Scholar 

  • McKerrow JH, Sun E, Rosenthal PJ, Bouvier J (1993) The proteases and pathogenicity of parasitic protozoa. Annu Rev Microbiol 47:821–853

    Article  PubMed  CAS  Google Scholar 

  • Meldal M, Svendsen I, Breddam K, Auzanneau FI (1994) Portion-mixing peptide libraries of quenched fluorogenic substrates for complete subsite mapping of endoprotease specificity. Proc Natl Acad Sei USA 91:3314–3318

    Article  CAS  Google Scholar 

  • Murphy AM, Dagnino R, Vallar PL, Trippe AJ, Sherman SL, Lumpkin RH, Tamura SY, Webb TR (1992) Automated synthesis of peptide C-terminal aldehydes. J Am Chem Soc 114:3156–3157

    Article  CAS  Google Scholar 

  • Murray MC, Perkins ME (1996) Chemotherapy of malaria. Annu Rep Med Chem 31:141–150

    Article  CAS  Google Scholar 

  • Neurath H (1999) Proteolytic enzymes, past and future. Proc Natl Acad Sei U S A 96:10962–10963

    Article  CAS  Google Scholar 

  • Otto H-H, Schirmeister T (1997) Cysteine proteases and their inhibitors. Chem Rev 97:133–171

    Article  PubMed  CAS  Google Scholar 

  • Owens RA, Gesellchen PD, Houchins BJ, DiMarchi RD (1991) The rapid identification of HIV protease inhibitors through the synthesis and screening of defined peptide mixtures. Biochem Biophys Res Commun 181:402–408

    Article  PubMed  CAS  Google Scholar 

  • Rano TA, Timkey T, Peterson EP, Rotonda J, Nicholson DW, Becker JW, Chapman KT, Thornberry NA (1997) A combinatorial approach for determining protease specificities: application to interleukin-1 beta converting enzyme (ICE). Chem Biol 4:149–155

    Article  PubMed  CAS  Google Scholar 

  • Schellenberger V, Turck CW, Hedstrom L, Rutter WJ (1993) Mapping the S’ subsites of serine proteases using acyl transfer to mixtures of peptide nu-cleophiles. Biochemistry 32:4349–353

    Article  PubMed  CAS  Google Scholar 

  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    Article  PubMed  CAS  Google Scholar 

  • Troncoso JC, Cataldo AM, Nixon RA, Barnett JL, Lee MK, Checler F, Fowler DR, Smialek JE, Crain B, Martin LJ (1998) Neuropathology of preclinical and clinical late-onset Alzheimer’s disease. Ann Neurol 43:673–676

    Article  PubMed  CAS  Google Scholar 

  • Whittaker M (1998) Discovery of protease inhibitors using targeted libraries. Curr Opin Chem Biol 2(3):386–396

    Article  PubMed  CAS  Google Scholar 

  • Wyler DJ (1993) Malaria-overview and update. Clin Infect Dis 16:449–458

    Article  PubMed  CAS  Google Scholar 

  • Yamashita DS, Smith WW, Zhao B, Janson CA, Tomaszek TA, Bossard MJ, Levy MA, Oh H, Carr TJ, Thompson SK, Ijames CF, Carr SA, McQueney M, D’Alessio KJ, Amegadzie BY, Hanning CR, Abdel-Meguid S, Des Jarlais RL, Gleason JG, Veber DF (1997) Structure and design of potent and selective cathepsin K inhibitors. J Am Chem Soc 119:11351–11352

    Article  CAS  Google Scholar 

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Authors
  1. J. A. Ellman
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Editor information

Editors and Affiliations

  1. Institut für Organische Chemie, Universität Wien, Währinger Str. 38, 1090, Wien, Austria

    J. Mulzer

  2. Preclinical Drug Research, Schering AG, Müllerstr. 178, 13342, Berlin, Germany

    R. Bohlmann

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© 2000 Springer-Verlag Berlin Heidelberg

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Ellman, J.A. (2000). Combinatorial Methods to Engineer Small Molecules for Functional Genomics. In: Mulzer, J., Bohlmann, R. (eds) The Role of Natural Products in Drug Discovery. Ernst Schering Research Foundation Workshop, vol 32. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04042-3_6

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  • DOI: https://doi.org/10.1007/978-3-662-04042-3_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-04044-7

  • Online ISBN: 978-3-662-04042-3

  • eBook Packages: Springer Book Archive

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