Nature Chemical Biology 2018-04-09

A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells

Aaron H. Nile, Felipe de Sousa e Melo, Susmith Mukund, Robert Piskol, Simon Hansen, Lijuan Zhou, Yingnan Zhang, Yue Fu, Emily B. Gogol, László G. Kömüves, Zora Modrusan, Stephane Angers, Yvonne Franke, Christopher Koth, Wayne J. Fairbrother, Weiru Wang, Frederic J. de Sauvage, Rami N. Hannoush

Index: 10.1038/s41589-018-0035-2

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Abstract

Regeneration of the adult intestinal epithelium is mediated by a pool of cycling stem cells, which are located at the base of the crypt, that express leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5). The Frizzled (FZD) 7 receptor (FZD7) is enriched in LGR5+ intestinal stem cells and plays a critical role in their self-renewal. Yet, drug discovery approaches and structural bases for targeting specific FZD isoforms remain poorly defined. FZD proteins interact with Wnt signaling proteins via, in part, a lipid-binding groove on the extracellular cysteine-rich domain (CRD) of the FZD receptor. Here we report the identification of a potent peptide that selectively binds to the FZD7 CRD at a previously uncharacterized site and alters the conformation of the CRD and the architecture of its lipid-binding groove. Treatment with the FZD7-binding peptide impaired Wnt signaling in cultured cells and stem cell function in intestinal organoids. Together, our data illustrate that targeting the lipid-binding groove holds promise as an approach for achieving isoform-selective FZD receptor inhibition.