Fusion of two distinct peptide exosite inhibitors of Factor VIIa

The Biochemical Journal
M RobergeRobert A Lazarus

Abstract

Highly potent bifunctional inhibitors of Factor VIIa (FVIIa) were generated by linking two distinct peptides, recently shown to bind to two discrete exosites on the FVIIa protease domain [Dennis, Eigenbrot, Skelton, Ultsch, Santell, Dwyer, O'Connell and Lazarus (2000) Nature (London) 404, 465-470; Dennis, Roberge, Quan and Lazarus (2001) Biochemistry 40, 9513-9521; Roberge, Santell, Dennis, Eigenbrot, Dwyer and Lazarus (2001) Biochemistry 40, 9522-9531]. Fusion peptides consisting of an N-terminal A-series peptide followed by flexible linkers, an E-series peptide, and the Z-domain of protein A were expressed in Escherichia coli and purified using IgG-Sepharose affinity chromatography. The fusion peptides were potent anticoagulants and had steep concentration dependence curves in tissue factor-dependent prothrombin time (PT) assays in comparison to the individual peptides or their noncovalent combination. This phenomenon was dependent on the length of the linker joining the A- and E-peptides. The fusion of the peptides increased the extent of inhibition of Factor X (FX) activation to 100% at saturating peptide concentrations, but did not improve the binding affinity for Factor VIIa (FVIIa) at the A- and E- binding sites or the I...Continue Reading

References

Dec 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·B Osterud, S I Rapaport
May 30, 1991·The New England Journal of Medicine·J Hirsh
Nov 1, 1989·Analytical Biochemistry·S C Gill, P H von Hippel
Sep 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·L V Rao, S I Rapaport
Feb 13, 1996·Biochemistry·S Butenas, K G Mann
Sep 4, 1997·The New England Journal of Medicine·J I Weitz
Jul 1, 1998·Coronary Artery Disease·K Johnson, D Hung
Apr 13, 2000·Nature·M S DennisR A Lazarus
May 23, 2001·Trends in Cardiovascular Medicine·M T Wiiger, H Prydz

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Citations

Feb 16, 2012·The Journal of Biological Chemistry·Bruce SullengerDougald M Monroe
Mar 12, 2011·British Journal of Clinical Pharmacology·Ilka Ott
Jul 7, 2007·Expert Opinion on Therapeutic Targets·Robert A CopelandPeter J Tummino
Mar 6, 2009·Journal of Structural Biology·Sobhan RoyAmit Kumar Das
Mar 27, 2003·The Journal of Biological Chemistry·Henry R MaunRobert A Lazarus
Sep 25, 2004·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Karl-Erik Eilertsen, Bjarne Østerud

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