De Novo Design of a Potent Wnt Surrogate Specific for the Frizzled7 Subtype Members

The study presents a novel Wnt surrogate specifically designed for the Frizzled7 (Fzd7) receptor subtype, composed of three de novo designed modules: a Fzd7 binder, an LRP6 binder, and a homodimeric protein. This surrogate demonstrates high selectivity and affinity (K D < 2.3 nM) for Fzd7 and closely related subtypes (Fzd1, Fzd2), without binding to other Fzd receptors. It effectively induced spheroid organoid formation from intestinal stem cells and promoted full hair follicle regeneration and robust hair growth in mice. The findings suggest that this approach could be used to create modular Wnt surrogates for selective activation of individual Fzd receptors, offering a valuable tool for development, differentiation, organoid cultures, and targeted regeneration.