Development of small-molecule Wnt mimetics for corneal epithelial cell regeneration

项目摘要/摘要补充

Project Summary/Abstract for supplement The goal of the parent funding is to develop small-molecule Wnt mimics to increase the efficiency of expansion of functional human limbal stem cells (LSCs) or corneal epithelial stem/progenitor cells (CESCs) for transplantation into humans. The approach of creating Wnt mimics is to link two small molecules that bind to two Wnt co-receptors, Frizzled and LRP5/6, respectively. During the study, we found that gallic acid and digallic acid bind to Wnt co-receptor LRP5/6. There are four b-propeller domains in the extracellular domain of LRP5/6. Wnt molecules bind to the second b-propeller domain, whereas DKK proteins, one group of well- established Wnt antagonists, target the third b-propeller domain. All four b-propeller domains are structurally similar, but they are different. Therefore, a small-molecule that binds to the second b-propeller domain with the highest affinity is a Wnt inhibitor, whereas a small-molecule that binds to the third b-propeller domain with the highest affinity is an inhibitor of DKK. An inhibitor of inhibitor, the molecule is a Wnt activator. Using computational and cell biology approaches, we propose to analyze gallic acid-related natural products for their Wnt inhibition and activation activity. As inappropriate activation of Wnt signaling has been implicated in cancers and many other human diseases, the study may be helpful in exploring a broad therapeutic application for gallic acid and related compounds.