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PEDS Advance Access originally published online on August 8, 2005
Protein Engineering Design and Selection 2005 18(9):417-424; doi:10.1093/protein/gzi049
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases

A. Shrivastava1,2, M.A. von Wronski1, A.K. Sato3, D.T. Dransfield3, D. Sexton3, N. Bogdan1, R. Pillai1, P. Nanjappan1, B. Song1, E. Marinelli1, D. DeOliveira3, C. Luneau3, M. Devlin3, A. Muruganandam3, A. Abujoub3, G. Connelly3, Q.L. Wu3, G. Conley3, Q. Chang3, M.F. Tweedle1, R.C. Ladner3, R.E. Swenson1 and A.D. Nunn1

1Ernst Felder Laboratories, Bracco Research USA, 305 College Road East, Princeton, NJ 08540 and 3Dyax Corp., 300 Technology Square, Cambridge, MA 02139, USA

2 To whom correspondence should be addressed. E-mail: ajay.shrivastava{at}bru.bracco.com

We describe a novel and general way of generating high affinity peptide (HAP) binders to receptor tyrosine kinases (RTKs), using a multi-step process comprising phage-display selection, identification of peptide pairs suitable for hetero-dimerization (non-competitive and synergistic) and chemical synthesis of heterodimers. Using this strategy, we generated HAPs with KDs below 1 nM for VEGF receptor-2 (VEGFR-2) and c-Met. VEGFR-2 HAPs bound significantly better (6- to 500-fold) than either of the individual peptides that were used for heterodimer synthesis. Most significantly, HAPs were much better (150- to 800-fold) competitors than monomers of the natural ligand (VEGF) in various competitive binding and functional assays. In addition, we also found the binding of HAPs to be less sensitive to serum than their component peptides. We believe that this method may be applied to any protein for generating high affinity peptide (HAP) binders.

Keywords: c-MET/HAPs/heterodimer/peptide/VEGFR-2

Received March 4, 2005; revised July 13, 2005; accepted July 16, 2005.

Edited by Laurent Jespers


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