A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1 alpha stability. Here, the authors design a small molecule that stabilizes HIF1 alpha by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes. Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1 alpha (HIF-1 alpha). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL-HIF-1 alpha interaction. Furthermore, the compound accumulates HIF-1 alpha levels in cellulo and activates HIF-1 alpha mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1 alpha driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1 alpha as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1 alpha interaction.