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Structure-guided design of peptide-based tryptase inhibitors.

McGrath ME, Sprengeler PA, Hirschbein B, Somoza JR, Lehoux I, Janc JW, Gjerstad E, Graupe M, Estiarte A, Venkataramani C, Liu Y, Yee R, Ho JD, Green MJ, Lee CS, Liu L, Tai V, Spencer J, Sperandio D, Katz BA
Biochemistry 45 5964-73 (2006)
Related entries: 2fpz, 2fs8, 2fww, 2fx4, 2fx6, 2fxr

Cited: 11 times
EuropePMC logo PMID: 16681368

Abstract

Improved peptide-based inhibitors of human beta tryptase were discovered using information gleaned from tripeptide library screening and structure-guided design methods, including fragment screening. Our efforts sought to improve this class of inhibitors by replacing the traditional Lys or Arg P1 element. The optimized compounds display low nanomolar potency against the mast cell target and several hundred-fold selectivity with respect to serine protease off targets. Thus, replacement of Lys/Arg at P1 in a peptide-like scaffold does not need to be accompanied by a loss in target affinity.

Articles - 2fs9 mentioned but not cited (1)

  1. Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity. Fu Z, Akula S, Thorpe M, Hellman L. Int J Mol Sci 20 (2019)


Articles citing this publication (10)

  1. Purification and characterization of fibrinolytic alkaline protease from Fusarium sp. BLB. Ueda M, Kubo T, Miyatake K, Nakamura T. Appl. Microbiol. Biotechnol. 74 331-338 (2007)
  2. Binding affinities in the SAMPL3 trypsin and host-guest blind tests estimated with the MM/PBSA and LIE methods. Mikulskis P, Genheden S, Rydberg P, Sandberg L, Olsen L, Ryde U. J. Comput. Aided Mol. Des. 26 527-541 (2012)
  3. Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries. Jiang QQ, Sicking W, Ehlers M, Schmuck C. Chem Sci 6 1792-1800 (2015)
  4. Design and evaluation of Trypanosoma brucei metacaspase inhibitors. Berg M, Van der Veken P, Joossens J, Muthusamy V, Breugelmans M, Moss CX, Rudolf J, Cos P, Coombs GH, Maes L, Haemers A, Mottram JC, Augustyns K. Bioorg. Med. Chem. Lett. 20 2001-2006 (2010)
  5. Development of tryptase inhibitors derived from thalidomide. Tetsuhashi M, Ishikawa M, Hashimoto M, Hashimoto Y, Aoyama H. Bioorg. Med. Chem. 18 5323-5338 (2010)
  6. Predicting subsite interactions of plasmin with substrates and inhibitors through computational docking analysis. Gohda K, Teno N, Wanaka K, Tsuda Y. J Enzyme Inhib Med Chem 27 571-577 (2012)
  7. Solid phase synthesis of peptides containing novel amino acids, substituted 3-benzimidazolealanines. Koprowska-Ratajska M, Kluczyk A, Stefanowicz P, Bartosz-Bechowski H, Szewczuk Z. Amino Acids 36 309-315 (2009)
  8. Expedient on-resin synthesis of peptidic benzimidazoles. Bird MJ, Silvestri AP, Dawson PE. Bioorg. Med. Chem. Lett. 28 2679-2681 (2018)
  9. Dual functionality of β-tryptase protomers as both proteases and cofactors in the active tetramer. Maun HR, Liu PS, Franke Y, Eigenbrot C, Forrest WF, Schwartz LB, Lazarus RA. J. Biol. Chem. 293 9614-9628 (2018)
  10. Searching for Chymase Inhibitors among Chamomile Compounds Using a Computational-Based Approach. Dubey A, Dotolo S, Ramteke PW, Facchiano A, Marabotti A. Biomolecules 9 (2018)


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