Peptide exosite inhibitors of factor VIIa as anticoagulants

Mark S. Dennis, Charles Eigenbrot, Nicholas J. Skelton, Mark H. Ultsch, Lydia Santell, Mary A. Dwyer, Mark P. O'Connell and Robert A. Lazarus ()
Additional contact information
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.
Mark P. O'Connell: Genentech Inc.
Robert A. Lazarus: Genentech Inc.

Nature, 2000, vol. 404, issue 6777, 465-470

Abstract: 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.

Date: 2000
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DOI: 10.1038/35006574

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