Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M203415200 on May 14, 2002

J. Biol. Chem., Vol. 277, Issue 30, 27232-27239, July 26, 2002
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
277/30/27232    most recent
M203415200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Villard, S.
Right arrow Articles by Granier, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Villard, S.
Right arrow Articles by Granier, C.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Low Molecular Weight Peptides Restore the Procoagulant Activity of Factor VIII in the Presence of the Potent Inhibitor Antibody ESH8*

Sylvie Villard, Dominique Piquer, Sanjee RautDagger , Jean-Paul Léonetti, Jean-Marie Saint-Remy§, and Claude Granier

From the Unité Mixte de Recherche, CNRS 5094, Faculté de Pharmacie, BP 14491, 34093 Montpellier, France, Dagger  the Division of Haematology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom, and the § Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium

Following repeated administration of factor VIII (FVIII), a significant number of hemophilia A patients develop antibodies (Abs), inhibiting the procoagulant activity of infused FVIII. We have designed an approach based on the blocking of the deleterious activity of these Abs by peptide decoys mimicking the anti-FVIII Ab epitopes. Here, the well characterized inhibitory monoclonal Ab ESH8 served as a model. Several phage peptide libraries were screened for specific binding to ESH8. Seven constrained dodecapeptide sequences were obtained. Six sequences carried the consensus motif, hydrophobic-(Y/F)GKTXL. This motif showed a certain similarity with the 2231QVDFQKTMKV2240 sequence of the C2 domain. In the seventh sequence, YCNPSIGDKNCR, the residues GDKN are similar to the sequence 2267DGHQ2270. Upon inspection of the C2 domain crystallographic structure, the two stretches QVDFQKTMKV and DGHQ appeared close together in space and might constitute a discontinuous epitope. Corresponding synthetic peptides were able to inhibit the binding of ESH8 to FVIII in a specific and dose-dependent manner. Moreover, the ability of the selected peptides to neutralize the inhibitory activity of ESH8 was demonstrated in functional tests as well as in vivo in a murine model of hemophilia A. This study demonstrates the potential of this approach to neutralize the activity of potent inhibitory Abs.

* This work was partly supported by a grant from Wyeth.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: UMR CNRS 5094, Faculté de Pharmacie, BP 14491, 15 Ave. Charles Flahault, 34093 Montpellier Cedex 5, France. Tel.: 33-4-67-54-86-02; Fax: 33-4-67-54-86-10; E-mail: claude.granier@ibph.pharma.univ-montp1.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
S. Planque, M. A. Escobar, K. C. Smith, H. Taguchi, Y. Nishiyama, E. Donnachie, K. P. Pratt, and S. Paul
Covalent Inactivation of Factor VIII Antibodies from Hemophilia A Patients by an Electrophilic FVIII Analog
J. Biol. Chem., May 2, 2008; 283(18): 11876 - 11886.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Lacroix-Desmazes, B. Wootla, S. Dasgupta, S. Delignat, J. Bayry, J. Reinbolt, J. Hoebeke, E. Saenko, M. D. Kazatchkine, A. Friboulet, et al.
Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII
J. Immunol., July 15, 2006; 177(2): 1355 - 1363.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. C. Lei and D. W. Scott
Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins
Blood, June 15, 2005; 105(12): 4865 - 4870.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Vanhoorelbeke, H. Depraetere, R. A. P. Romijn, E. G. Huizinga, M. De Maeyer, and H. Deckmyn
A Consensus Tetrapeptide Selected by Phage Display Adopts the Conformation of a Dominant Discontinuous Epitope of a Monoclonal Anti-VWF Antibody That Inhibits the von Willebrand Factor-Collagen Interaction
J. Biol. Chem., September 26, 2003; 278(39): 37815 - 37821.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement