Repurposing of hypoxia-inducible factor-1 prolyl hydroxylase inhibitor for treatment of diabetic wounds
摘要
Diabetic wound is one of the serious microvascular complications associated with diabetes mellitus. Desidustat belongs to the Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitor class of drugs currently used for the treatment of anemia associated with chronic kidney disease and is reported to promote angiogenesis. Therefore, the present study aimed to evaluate desidustat for the treatment of diabetes associated wound healing.
MethodsDesidustat was docked with target proteins using PyRx and GOLD software. The interactions were visualized in Discovery Studio Visualizer. Further, an in-vitro cell viability assay was performed to find the potential dose, followed by a scratch wound closure assay, transwell migration assay, colony formation assay, and polymerase chain reaction to assess gene expression. Desidustat was further examined using ex vivo chick chorioallantoic membrane assay and in vivo using zebrafish tail fin regeneration.
ResultsThe docking study showed strong binding affinity to growth factors involved in angiogenic pathways. In in-vitro assay, desidustat demonstrated enhanced scratch closure, increased cell migration in transwell migration assay, and increased cell survival and migration in colony formation assays. Gene expression study confirmed upregulation of vascular endothelial growth factor expression in the cell line. Further, CAM assays also showed increased blood vessel formation, and zebrafish experiments exhibited complete tail fin regeneration, indicating that desidustat has a good regenerative potential.
ConclusionDesidustat exhibits significant angiogenic and regenerative potential, supporting its possible therapeutic application in the management of diabetic wounds and ulcers.