Inhibitors of human heart chymase based on a peptide library.

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  • Author(s): Bastos M;Bastos M; Maeji NJ; Abeles RH
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1995 Jul 18; Vol. 92 (15), pp. 6738-42.
  • Publication Type:
    Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Serine Endopeptidases*; Myocardium/*enzymology ; Peptides/*pharmacology ; Serine Proteinase Inhibitors/*pharmacology; Amino Acid Sequence ; Binding Sites/drug effects ; Chymases ; Evaluation Studies as Topic ; Humans ; Isoleucine/analogs & derivatives ; Molecular Sequence Data ; Phenylalanine/analogs & derivatives ; Pyruvates/chemistry ; Reproducibility of Results ; Serine Proteinase Inhibitors/chemistry
    • Abstract:
      We have synthesized two sets of noncleavable peptide-inhibitor libraries to map the S and S' subsites of human heart chymase. Human heart chymase is a chymotrypsin-like enzyme that converts angiotensin I to angiotensin II. The first library consists of peptides with 3-fluorobenzylpyruvamides in the P1 position. (Amino acid residues of substrates numbered P1, P2, etc., are toward the N-terminal direction, and P'1, P'2, etc., are toward the C-terminal direction from the scissile bond.) The P'1 and P'2 positions were varied to contain each one of the 20 naturally occurring amino acids and P'3 was kept constant as an arginine. The second library consists of peptides with phenylalanine keto-amides at P1, glycine in P'1, and benzyloxycarbonyl (Z)-isoleucine in P4. The P2 and P3 positions were varied to contain each of the naturally occurring amino acids, except for cysteine and methionine. The peptides of both libraries are attached to a solid support (pins). The peptides are evaluated by immersing the pins in a solution of the target enzyme and evaluating the amount of enzyme absorbed. The pins with the best inhibitors will absorb most enzyme. The libraries select the best and worst inhibitors within each group of peptides and provide an approximate ranking of the remaining peptides according to Ki. Through this library, we determined that Z-Ile-Glu-Pro-Phe-CO2Me and (F)-Phe-CO-Glu-Asp-ArgOMe should be the best inhibitors of chymase in this collection of peptide inhibitors. We synthesized the peptides and found Ki values were 1 nM and 1 microM, respectively. The corresponding Ki values for chymotrypsin were 10 nM and 100 microM. The use of libraries of inhibitors has advantages over the classical method of synthesis of potential inhibitors in solution: the libraries are reusable, the same libraries can be used with a variety of different serine proteases, and the method allows the screening of hundreds of compounds in short periods of time.
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    • Grant Information:
      GM12633-31 United States GM NIGMS NIH HHS; R01 HL44201-02 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Peptides)
      0 (Pyruvates)
      0 (Serine Proteinase Inhibitors)
      04Y7590D77 (Isoleucine)
      47E5O17Y3R (Phenylalanine)
      EC 3.4.21.- (Serine Endopeptidases)
      EC 3.4.21.39 (Chymases)
    • Publication Date:
      Date Created: 19950718 Date Completed: 19950831 Latest Revision: 20190501
    • Publication Date:
      20250114
    • Accession Number:
      PMC41404
    • Accession Number:
      10.1073/pnas.92.15.6738
    • Accession Number:
      7624313