Journal Article

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

Wong, Vincent Kam Wai, Li, Dan, Lin, Ligen, Ko, Chung-Nga, Xiang, Yaozu, Ma, Dik-Lung, Wang, Wanhe, Yang, Chao, Yang, Guan-Jun, Di Primo, Carmelo, Li, Guodong, Leung, Chung-Hang

2021

Overview

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-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α 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-1α 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-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction. Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/77 / 631/154 / 692/163/2743/137 / 692/699/4033 / 82/80 / 82/83 / Animal models / Animals / Chemical compounds / Coordination Complexes - chemistry / Coordination Complexes - pharmacology / Coordination compounds / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Experimental - pathology / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Gene expression / Gene Expression - drug effects / HEK293 Cells / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Iridium / Iridium - chemistry / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Pharmacology / Protein Binding - drug effects / Science / Science (multidisciplinary) / SDF-1 protein / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Vascular endothelial growth factor / Vascular endothelial growth factor receptors / VHL protein / Von Hippel-Lindau Tumor Suppressor Protein - metabolism / Wound healing / Wound Healing - drug effects / Wound Healing - genetics