Abstract
Matrix metalloproteinase (MMP) and soluble epoxide hydrolase (sEH) have completely unrelated biological functions, however, their dysregulation produce similar effects on biological systems. Based on the similarity in the reported structural requirements for their inhibition, the current study aimed to identify a simultaneous inhibitor for MMP and sEH. Six compounds were identified as potential simultaneous MMP/sEH inhibitors and tested for their capacity to inhibit MMP and sEH. Inhibition of MMP and sEH activity using their endogenous and exogenous substrates was measured by liquid chromatography/mass spectrometry, spectrophotometry and zymography. Two compounds, CTK8G1143 and ONO-4817, were identified to inhibit both MMP and sEH activity. CTK8G1143 and ONO-4817 inhibited the recombinant human sEH activity by an average of 67.4% and 55.2%, respectively. The IC50 for CTK8G1143 and ONO-4817 to inhibit recombinant human sEH were 5.2 and 3.5 µM, respectively, whereas, their maximal inhibition values were 71.4% and 42.8%, respectively. Also, MMP and sEH activity of human cardiomyocytes were simultaneously inhibited by CTK8G1143 and ONO-4817. Regarding other compounds, they showed either MMP or sEH inhibitory activity but not both. In conclusion, these two simultaneous inhibitors of MMP and sEH could provide a promising intervention for the prevention and control of several diseases, especially cardiovascular diseases. This work was supported by a grant from the CIHR to AOSE.
Highlights
Matrix metalloproteinases (MMP) comprise a family of more than 20 zinc-dependent endopeptidases best known for their ability to mediate degradation of extracellular matrix (Jabłońska-Trypuć, Matejczyk, & Rosochacki, 2016; Laronha & Caldeira, 2020; X. Wang & Khalil, 2018)
CTK8G1143 and ONO-4817 inhibited soluble epoxide hydrolase (sEH) activity by 59.8% and 71.2%, respectively, whereas the potent sEH inhibitor, Trans-4-[4-(3Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), inhibited sEH activity by 85.5% compared with dimethyl sulfoxide (DMSO) control (Fig. 1A)
Using 14,15-epoxyeicosatrienoic acids (EETs), which is the endogenous substrate of sEH, CTK8G1143 and ONO-4817 inhibited sEH activity by 74.9% and 39.1%, respectively, and t-AUCB inhibited sEH activity by 84.2% compared with DMSO control (Fig. 1A)
Summary
Matrix metalloproteinases (MMP) comprise a family of more than 20 zinc-dependent endopeptidases best known for their ability to mediate degradation of extracellular matrix (Jabłońska-Trypuć, Matejczyk, & Rosochacki, 2016; Laronha & Caldeira, 2020; X. Wang & Khalil, 2018). Matrix metalloproteinases (MMP) comprise a family of more than 20 zinc-dependent endopeptidases best known for their ability to mediate degradation of extracellular matrix Extracellular matrix consists of a collection of fibrous proteins, collagen and enzymes imbedded in a hydrated polysaccharide gel, and provides the required structural and biochemical support to cells to form tissues and organs (Kular, Basu, & Sharma, 2014; Laronha & Caldeira, 2020). Soluble epoxide hydrolase (sEH) is the enzyme responsible for the inactivation of a group of important lipid mediators, namely epoxyeicosatrienoic acids (EETs) Capdevila & Wang, 2013; Xu et al, 2016). The formation of EETs is mediated by cytochrome P450 enzymes, typically CYP2Cs and CYP2Js, from arachidonic acid 2013; Yang et al, 2014)
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