Jie Ding, Sung-Jin Lee, Lukas Vlahos, Kanako Yuki, Cara C Rada, Vincent van Unen, Meghah Vuppalapaty, Hui Chen, Asmiti Sura, Aaron K McCormick, Madeline Tomaske, Samira Alwahabi, Huy Nguyen, William Nowatzke, Lily Kim, Lisa Kelly, Douglas Vollrath, Andrea Califano, Wen-Chen Yeh, Yang Li, Calvin J Kuo
Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD4 /TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4 -selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD4 -specific surrogate which significantly improves subpicomolar affinity versus native Norrin...
June 2, 2023: Nature Communications