Identifying simultaneous matrix metalloproteinases/soluble epoxide hydrolase inhibitors.

Ahmed A El-Sherbeni,Fadumo A Isse,Rabia Bhatti,Ayman O S El-Kadi

doi:10.1007/s11010-021-04337-5

Ahmed A El-Sherbeni, Fadumo A Isse + Show 2 more

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https://doi.org/10.1007/s11010-021-04337-5

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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 values for CTK8G1143 and ONO-4817 to inhibit recombinant human sEH were 5.2 and 3.5µM, 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.

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

Introduction

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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