Coagulation proteases are involved in a highly orchestrated proteolytic cascade which is essential for haemostasis and blood clotting. In particular, the initiator of the coagulation cascade, Factor VIIa, binds to its cofactor, tissue factor, and its substrate, Factor X, via exosite interactions to form a ternary catalytic complex named extrinsic Xase. These exosite interactions have also been shown to allosterically induce the active conformation of the catalytic site of Factor VIIa. We have developed a direct continuous fluorescence polarization-based extrinsic Xase assay, which has been used to screen in excess of 1 million structurally diverse low-molecular-mass compounds as a potential starting point for the development of anticoagulants. The primary screen hits were categorized with deconvolution assays into either active-site or exosite inhibitors. The latter category of hits displayed both competitive and uncompetitive modalities of inhibition with respect to Factor X activation. An uncompetitive mechanism of action is of particular interest as it offers a hypothetical inhibitory advantage in the context of inhibiting a proteolytic cascade such as the blood coagulation pathway.
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June 2007
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Conference Article|
May 22 2007
The quest for Factor VIIa exosite inhibitors
A. Amour;
A. Amour
1
*GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, U.K.
1To whom correspondence should be addressed (email [email protected]).
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J. Hutchinson;
J. Hutchinson
†GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, U.K.
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A.M. Ruiz Avendaño;
A.M. Ruiz Avendaño
‡GlaxoSmithKline, Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos Madrid, Spain
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S. Ratcliffe;
S. Ratcliffe
*GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, U.K.
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E. Alvarez;
E. Alvarez
‡GlaxoSmithKline, Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos Madrid, Spain
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J. Martin;
J. Martin
‡GlaxoSmithKline, Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760 Tres Cantos Madrid, Spain
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J.R. Toomey;
J.R. Toomey
§GlaxoSmithKline, King of Prussia, PA 19406, U.S.A.
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S. Senger;
S. Senger
*GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, U.K.
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M. Wolfendale;
M. Wolfendale
*GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, U.K.
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C. Mooney
C. Mooney
*GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, U.K.
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Publisher: Portland Press Ltd
Received:
March 13 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (3): 555–558.
Article history
Received:
March 13 2007
Citation
A. Amour, J. Hutchinson, A.M. Ruiz Avendaño, S. Ratcliffe, E. Alvarez, J. Martin, J.R. Toomey, S. Senger, M. Wolfendale, C. Mooney; The quest for Factor VIIa exosite inhibitors. Biochem Soc Trans 1 June 2007; 35 (3): 555–558. doi: https://doi.org/10.1042/BST0350555
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