- Author
- Year
- 2015
- Title
- Reconstructing the Discontinuous and Conformational β1/β 3-Loop Binding Site on hFSH/hCG by Using Highly Constrained Multicyclic Peptides
- Journal
- ChemBioChem
- Volume | Issue number
- 16 | 1
- Pages (from-to)
- 91-99
- Document type
- Article
- Faculty
- Faculty of Science (FNWI)
- Institute
- Van 't Hoff Institute for Molecular Sciences (HIMS)
- 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.
- URL
- go to publisher's site
- Language
- English
- Note
- with supporting information
- Permalink
- http://hdl.handle.net/11245/1.473664
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