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Peptide exosite inhibitors of factor VIIa as anticoagulants

Author

Listed:
  • Mark S. Dennis

    (Genentech Inc.)

  • Charles Eigenbrot

    (Genentech Inc.)

  • Nicholas J. Skelton

    (Genentech Inc.)

  • Mark H. Ultsch

    (Genentech Inc.)

  • Lydia Santell

    (Genentech Inc.)

  • Mary A. Dwyer

    (Genentech Inc.
    University of Chicago)

  • Mark P. O'Connell

    (Genentech Inc.)

  • Robert A. Lazarus

    (Genentech Inc.)

Abstract

Potent anticoagulants have been derived by targeting the tissue factor–factor VIIa complex with naive peptide libraries displayed on M13 phage. The peptides specifically block the activation of factor X with a median inhibitory concentration of 1 nM and selectively inhibit tissue-factor-dependent clotting. The peptides do not bind to the active site of factor VIIa; rather, they work by binding to an exosite on the factor VIIa protease domain, and non-competitively inhibit activation of factor X and amidolytic activity. One such peptide (E-76) has a well defined structure in solution determined by NMR spectroscopy that is similar to the X-ray crystal structure when complexed with factor VIIa. These structural and functional studies indicate an allosteric ‘switch’ mechanism of inhibition involving an activation loop of factor VIIa and represent a new framework for developing inhibitors of serine proteases.

Suggested Citation

  • Mark S. Dennis & Charles Eigenbrot & Nicholas J. Skelton & Mark H. Ultsch & Lydia Santell & Mary A. Dwyer & Mark P. O'Connell & Robert A. Lazarus, 2000. "Peptide exosite inhibitors of factor VIIa as anticoagulants," Nature, Nature, vol. 404(6777), pages 465-470, March.
    • Handle: RePEc:nat:nature:v:404:y:2000:i:6777:d:10.1038_35006574
    DOI: 10.1038/35006574
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    Cited by:

    1. Stefan Gerhardy & Mark Ultsch & Wanjian Tang & Evan Green & Jeffrey K. Holden & Wei Li & Alberto Estevez & Chris Arthur & Irene Tom & Alexis Rohou & Daniel Kirchhofer, 2022. "Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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