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

A. Shrivastava; M. A. Von Wronski; A. K. Sato; D. T. Dransfield; D. Sexton; N. Bogdan; R. Pillai; P. Nanjappan; B. Song; E. Marinelli; D. DeOliveira; C. Luneau; M. Devlin; A. Muruganandam; A. Abujoub; G. Connelly; Q. L. Wu; G. Conley; Q. Chang; M. F. Tweedle; R. C. Ladner; R. E. Swenson; A. D. Nunn

doi:10.1093/protein/gzi049

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

A. Shrivastava, M. A. Von Wronski, A. K. Sato, D. T. Dransfield, D. Sexton, N. Bogdan, R. Pillai, P. Nanjappan, B. Song, E. Marinelli, D. DeOliveira, C. Luneau, M. Devlin, A. Muruganandam, A. Abujoub, G. Connelly, Q. L. Wu, G. Conley, Q. Chang, M. F. TweedleR. C. Ladner, R. E. Swenson, A. D. Nunn

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

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 K_Ds 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.

Original language	English (US)
Pages (from-to)	417-424
Number of pages	8
Journal	Protein Engineering, Design and Selection
Volume	18
Issue number	9
DOIs	https://doi.org/10.1093/protein/gzi049
State	Published - Sep 2005
Externally published	Yes

Keywords

HAPs
Heterodimer
Peptide
VEGFR-2
c-MET

ASJC Scopus subject areas

General Medicine

Access to Document

10.1093/protein/gzi049

Cite this

Shrivastava, A., Von Wronski, M. A., Sato, A. K., Dransfield, D. T., Sexton, D., Bogdan, N., Pillai, R., Nanjappan, P., Song, B., Marinelli, E., DeOliveira, D., Luneau, C., Devlin, M., Muruganandam, A., Abujoub, A., Connelly, G., Wu, Q. L., Conley, G., Chang, Q., ... Nunn, A. D. (2005). A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases. Protein Engineering, Design and Selection, 18(9), 417-424. https://doi.org/10.1093/protein/gzi049

Shrivastava, A, Von Wronski, MA, Sato, AK, Dransfield, DT, Sexton, D, Bogdan, N, Pillai, R, Nanjappan, P, Song, B, Marinelli, E, DeOliveira, D, Luneau, C, Devlin, M, Muruganandam, A, Abujoub, A, Connelly, G, Wu, QL, Conley, G, Chang, Q, Tweedle, MF, Ladner, RC, Swenson, RE & Nunn, AD 2005, 'A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases', Protein Engineering, Design and Selection, vol. 18, no. 9, pp. 417-424. https://doi.org/10.1093/protein/gzi049

@article{fd49fb6340d54b7581716d1b1b10614f,

title = "A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases",

abstract = "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 = "HAPs, Heterodimer, Peptide, VEGFR-2, c-MET",

author = "A. Shrivastava and {Von Wronski}, {M. A.} and Sato, {A. K.} and Dransfield, {D. T.} and D. Sexton and N. Bogdan and R. Pillai and P. Nanjappan and B. Song and E. Marinelli and D. DeOliveira and C. Luneau and M. Devlin and A. Muruganandam and A. Abujoub and G. Connelly and Wu, {Q. L.} and G. Conley and Q. Chang and Tweedle, {M. F.} and Ladner, {R. C.} and Swenson, {R. E.} and Nunn, {A. D.}",

year = "2005",

month = sep,

doi = "10.1093/protein/gzi049",

language = "English (US)",

volume = "18",

pages = "417--424",

journal = "Protein Engineering, Design and Selection",

issn = "1741-0126",

publisher = "Oxford University Press",

number = "9",

}

TY - JOUR

T1 - A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases

AU - Shrivastava, A.

AU - Von Wronski, M. A.

AU - Sato, A. K.

AU - Dransfield, D. T.

AU - Sexton, D.

AU - Bogdan, N.

AU - Pillai, R.

AU - Nanjappan, P.

AU - Song, B.

AU - Marinelli, E.

AU - DeOliveira, D.

AU - Luneau, C.

AU - Devlin, M.

AU - Muruganandam, A.

AU - Abujoub, A.

AU - Connelly, G.

AU - Wu, Q. L.

AU - Conley, G.

AU - Chang, Q.

AU - Tweedle, M. F.

AU - Ladner, R. C.

AU - Swenson, R. E.

AU - Nunn, A. D.

PY - 2005/9

Y1 - 2005/9

N2 - 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.

AB - 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.

KW - HAPs

KW - Heterodimer

KW - Peptide

KW - VEGFR-2

KW - c-MET

UR - http://www.scopus.com/inward/record.url?scp=24044486898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24044486898&partnerID=8YFLogxK

U2 - 10.1093/protein/gzi049

DO - 10.1093/protein/gzi049

M3 - Article

C2 - 16087652

AN - SCOPUS:24044486898

SN - 1741-0126

VL - 18

SP - 417

EP - 424

JO - Protein Engineering, Design and Selection

JF - Protein Engineering, Design and Selection

IS - 9

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this