A small molecule HIF-1\u03b1 stabilizer that accelerates diabetic wound healing

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

doi:10.1038/s41467-021-23448-7

Abstract

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.

Highlights

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients
Complexes that inhibit the interaction between Von Hippel-Lindau (VHL) and hypoxia-inducible factor-1α (HIF-1α) would be expected to increase the level of hypoxia response element (HRE)-driven luciferase activity in the cell lysates
The Rh(III) complex Rh(brpy)2(dmeophen) 1 (where brpy = 2-(4-bromophenyl)pyridine and dmeophen = 4,7-dimethoxy-1,10-phenanthroline) emerged as the top candidate in the first round of screening (Fig. 1b), with slightly higher activity compared to the positive control compound, P1 ((2S)-4hydroxy-1-(2-(((Z)-2-(3-methoxybenzylidene)-3-oxo-2,3-dihydro benzofuran-6-yl)oxy)acetyl)pyrrolidine-2-carboxylic acid) (Supplementary Fig. 1), a previously reported inhibitor of the VHL–HIF-1α PPI discovered by our group[33]

Summary

Introduction

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. HIF-1α steady-state levels are low due to oxygen-dependent hydroxylation of HIF-1α by prolyl hydroxylase domain proteins (PHDs)[13] This allows HIF-1α to combine with Von Hippel-Lindau (VHL). Hyperglycemia can decrease the stability of HIF-1α, leading to the inhibition of HIF-1α target gene expression, which could account for the poor healing and ulcer complications in diabetic patients[16]. This suggests that strategies to improve the stability of HIF-1α, such as by blocking the interaction between VHL and HIF-1α, could be a promising strategy for the treatment of diabetes wound complications. PHDs inhibitors are associated with side effects, such as fatal liver necrosis for FG-

Methods

Results

Conclusion