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Issue 1, 2020
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Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a

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Abstract

Here we report de novo macrocyclic peptide binders to Wnt3a, a member of the Wnt protein family. By means of the Random non-standard Peptides Integrated Discovery (RaPID) system, we have performed in vitro selection against the complex of mouse Wnt3a (mWnt3a) with human afamin (hAFM) to discover macrocyclic peptides that bind mWnt3a with KD values as tight as 110 nM. One of these peptides, WAp-D04 (Wnt–AFM-peptide-D04), was able to inhibit the receptor-mediated signaling process, which was demonstrated in a Wnt3a-dependent reporter cell-line. Based on this initial hit, we applied a block-mutagenesis scanning display to identify a mutant inhibitor, WAp-D04-W10P, with 5-fold greater potency in a reporter assay. This work represents the first instance of molecules capable of inhibiting Wnt signaling through direct interaction with a Wnt protein, a molecular class for which targeting has been challenging due its highly hydrophobic nature.

Graphical abstract: Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a

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Supplementary files

Article information


Submitted
05 Feb 2020
Accepted
13 Mar 2020
First published
24 Mar 2020

This article is Open Access

RSC Chem. Biol., 2020,1, 26-34
Article type
Paper

Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a

M. E. Otero-Ramirez, K. Matoba, E. Mihara, T. Passioura, J. Takagi and H. Suga, RSC Chem. Biol., 2020, 1, 26
DOI: 10.1039/D0CB00016G

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