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

Guodong Li, Chung-Nga Ko, Dan Li, Chao Yang, Wanhe Wang, Guan-Jun Yang, Carmelo Di Primo, Vincent Kam Wai Wong, Yaozu Xiang, Ligen Lin (), Dik-Lung Ma () and Chung-Hang Leung ()
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Guodong Li: University of Macau
Chung-Nga Ko: Hong Kong Baptist University
Dan Li: University of Macau
Chao Yang: University of Macau
Wanhe Wang: Hong Kong Baptist University
Guan-Jun Yang: University of Macau
Carmelo Di Primo: University of Bordeaux
Vincent Kam Wai Wong: Macau University of Science and Technology
Yaozu Xiang: Tongji University
Ligen Lin: University of Macau
Dik-Lung Ma: Hong Kong Baptist University
Chung-Hang Leung: University of Macau

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23448-7

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