Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9

Abstract

In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.

A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integratedin silico,in vitro, andin vivostrategy

“…The FDA has approved bioengineered skin-care products such as Apligraf and Dermagra for treating diabetic foot ulcers (DFU). 28 FG-2216 is in clinical trials (IOX3), an effective and orally active inhibitor of HIF-1a prolyl hydroxylase-2 (PHD2) with an IC50 of 3.9 M. In vivo, FG-2216 produces high levels of erythropoietin and low levels of haemoglobin. 29 Previous research has demonstrated that hyperglycaemia inhibits HIF-1a ′ s activity in diabetic mice by destabilizing it through a VHL-dependent mechanism.…”

Discovery and evaluation of active compounds from Xuanfei Baidu formula against COVID-19 via SARS-CoV-2 Mpro

“…The excitation and emission wavelength were set at 320 and 405 nm, separately. The data was analyzed with Graphpad prism 9.0 and all experiments were performed in triplicates [ 16 ].…”

Epigenetic modification: A novel insight into diabetic wound healing

“…Proangiogenic factor expression is another thing that HMTs can influence. For instance, in hypoxic and hyperglycemic conditions, SET7/9 can methylate HIF-1α at lysine residue 32 and suppress the levels of hypoxia-inducible factor-1α (HIF-1α), which delays the healing of wounds [ 72 ]. Enhancer of zeste homolog 2 (EZH2), on the other hand, can stimulate HIF-1α H3K4me3 to raise HIF-1α expression, improve wound repair in diabetic rats wounds, and increase dermal fibroblast viability [ 73 ].…”