2. Academic Validation
  3. A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells

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

  • Nat Chem Biol. 2018 Jun;14(6):582-590. doi: 10.1038/s41589-018-0035-2.
Aaron H Nile 1,  Felipe de Sousa E Melo 2,  Susmith Mukund 3,  Robert Piskol 4,  Simon Hansen 1,  Lijuan Zhou 1,  Yingnan Zhang 1,  Yue Fu 1,  Emily B Gogol 1,  László G Kömüves 5,  Zora Modrusan 6,  Stephane Angers 7,  Yvonne Franke 8,  Christopher Koth 3,  Wayne J Fairbrother 1,  Weiru Wang 3,  Frederic J de Sauvage 2,  Rami N Hannoush 9
Affiliations

Affiliations

  • 1 Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA.
  • 2 Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
  • 3 Department of Structural Biology, Genentech, South San Francisco, CA, USA.
  • 4 Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA, USA.
  • 5 Department of Pathology, Genentech, South San Francisco, CA, USA.
  • 6 Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
  • 7 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
  • 8 Department of Biomolecular Resources, Genentech, South San Francisco, CA, USA.
  • 9 Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA. hannoush.rami@gene.com.
PMID: 29632413 DOI: 10.1038/s41589-018-0035-2
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.

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