**Background**
The Wnt signaling pathway plays a critical role in embryonic development, tissue homeostasis, and the maintenance of adult stem cells. Dysregulation of this pathway, particularly through the overactivation of Frizzled (FZD) receptors, is frequently implicated in various malignancies and developmental disorders. Among the Frizzled family, FZD7 has emerged as a significant target due to its involvement in Wnt-β-catenin signaling and its overexpression in several types of cancer. Selective inhibition of FZD7 is therefore a promising strategy for therapeutic intervention in cancer and the study of stem cell dynamics. In this context, we will introduce a potent FZD7 antagonist – Fz7-21.
**Definition**
Fz7-21 (Ac-LPSDDLEFWCHVMY-NH2) is a selective peptide antagonist that binds to the cysteine-rich domain (CRD) subclass of FZD7 receptors. It exhibits high potency with EC50 values of 58 nM for human FZD7 CRD and 34 nM for mouse FZD7 CRD.
**In Vitro Studies**
According to the Fz7-21 description, this peptide selectively binds to the FZD7 CRD and alters the conformation of the CRD as well as the architecture of its lipid-binding groove. In terms of Fz7-21 biological activity, in vitro experiments using HEK293-TB cells demonstrated that Fz7-21 (0-100 μM; 6 h) impairs Wnt signaling with an IC50 value of 100 nM. Furthermore, Fz7-21 (1 μM) was found to block the WNT3A-mediated stabilization of β-catenin in mouse L cells, exhibiting an IC50 value of 50 nM. Beyond signaling inhibition, Fz7-21 (200 μM; 48 h) effectively disrupts the function of LGR5+ stem cells in intestinal organoids. These results highlight the capacity of Fz7-21 to impair both the Wnt-β-catenin signaling pathway and essential stem cell functions. In conclusion, Fz7-21 is a potent and selective peptide inhibitor of FZD7 receptors suitable for research in Wnt signaling and cancer.
Keywords
Fz7-21, Ac-LPSDDLEFWCHVMY-NH2, Wnt, FZD7, conformation, lipid-binding groove, FZD7 CRD, Wnt–β-catenin, intestinal organoids, Inhibitor, inhibitor, inhibit
References
[1] Nile AH, et, al. A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells. Nat Chem Biol. 2018 Jun;14(6):582-590.
[2] Larasati Y, et, al. Unlocking the Wnt pathway: Therapeutic potential of selective targeting FZD7 in cancer. Drug Discov Today. 2022 Mar;27(3):777-792.