| First Author | Li G | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3363 |
| PubMed ID | 34099651 | Mgi Jnum | J:322190 |
| Mgi Id | MGI:6725363 | Doi | 10.1038/s41467-021-23448-7 |
| Citation | Li G, et al. (2021) A small molecule HIF-1alpha stabilizer that accelerates diabetic wound healing. Nat Commun 12(1):3363 |
| abstractText | 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-1alpha (HIF-1alpha). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL-HIF-1alpha interaction. Furthermore, the compound accumulates HIF-1alpha levels in cellulo and activates HIF-1alpha 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-1alpha 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-1alpha as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1alpha interaction. |
