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
  • 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. [email protected].
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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