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  • Title: Peptide exosite inhibitors of factor VIIa as anticoagulants.
    Author: Dennis MS, Eigenbrot C, Skelton NJ, Ultsch MH, Santell L, Dwyer MA, O'Connell MP, Lazarus RA.
    Journal: Nature; 2000 Mar 30; 404(6777):465-70. PubMed ID: 10761907.
    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.
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