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Reconstructing the Discontinuous and Conformational β1/β3-Loop Binding Site on hFSH/hCG by Using Highly Constrained Multicyclic Peptides

  1. Dr. Linde E. J. Smeenk1,
  2. Drohpatie Timmers-Parohi2,
  3. Dr. Joris J. Benschop2,
  4. Wouter C. Puijk2,
  5. Prof. Dr. Henk Hiemstra1,
  6. Dr. Jan H. van Maarseveen1 and
  7. Prof. Dr. Peter Timmerman1,2,*

Article first published online: 2 DEC 2014

DOI: 10.1002/cbic.201402540

Issue

ChemBioChem

ChemBioChem

Volume 16, Issue 1, pages 91–99, January 2, 2015


Additional Information

How to Cite

Smeenk, L. E. J., Timmers-Parohi, D., Benschop, J. J., Puijk, W. C., Hiemstra, H., van Maarseveen, J. H. and Timmerman, P. (2015), Reconstructing the Discontinuous and Conformational β1/β3-Loop Binding Site on hFSH/hCG by Using Highly Constrained Multicyclic Peptides. ChemBioChem, 16: 91–99. doi: 10.1002/cbic.201402540

Author Information

  1. 1

    Van't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam (Netherlands)

  2. 2

    Pepscan Therapeutics, Zuidersluisweg 2, 8243 Lelystad (Netherlands)

*Van't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam (Netherlands)

Publication History

  1. Issue published online: 23 DEC 2014
  2. Article first published online: 2 DEC 2014
  3. Manuscript Received: 17 SEP 2014

Funded by

  • The Netherlands Organization for Scientific Research (NWO). Grant Number: ECHO 700.57.017

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Keywords:

  • constrained peptides;
  • discontinuous epitope;
  • multicyclic peptides;
  • protein mimicry

Abstract

Making peptide-based molecules that mimic functional interaction sites on proteins remains a challenge in biomedical sciences. Here, we present a robust technology for the covalent assembly of highly constrained and discontinuous binding site mimics, the potential of which is exemplified for structurally complex binding sites on the “Cys-knot” proteins hFSH and hCG. Peptidic structures were assembled by Ar(CH2Br)2-promoted peptide cyclizations, combined with oxime ligation and disulfide formation. The technology allows unprotected side chain groups and is applicable to peptides of different lengths and nature. A tetracyclic FSH mimic was constructed, showing >600-fold improved binding compared to linear or monocyclic controls. Binding of a tricyclic hCG mimic to anti-hCG mAb 8G5 was identical to hCG itself (IC50=260 vs. 470 pM), whereas this mimic displayed an IC50 value of 149 nM for mAb 3468, an hCG-neutralizing antibody with undetectable binding to either linear or monocyclic controls.

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