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

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.

Polydopamine Decorated Microneedles with Fe‐MSC‐Derived Nanovesicles Encapsulation for Wound Healing

“…[ 31 ] HIF‐1 α is essential in angiogenesis because it induces multiple angiogenic genes. [ 32 , 33 ] Besides, TGF‐ β 3 promotes collagen organization to reduce scars and improve healing. [ 34 ] Therefore, these cytokines expressed in Fe‐MSC‐NVs collaboratively promote diabetic wound healing.…”

Inhibition of the CDK9–cyclin T1 protein–protein interaction as a new approach against triple-negative breast cancer

“…The method was performed as previously described 33 . The pull-down assay was performed by using a gravity flow column with GST-agarose beads.…”

Bioactive Materials Promote Wound Healing through Modulation of Cell Behaviors

“…According to the latest study, Li et al synthesized a cyclometallated iridium(III) metal complex 1a as a small molecule stabilizer of HIF‐1 α that binds to VHL and blocks their interactions. [ 114 ]…”