Synthetic Guaiacol Derivatives as Promising Myeloperoxidase Inhibitors Targeting Atherosclerotic Cardiovascular Disease

Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to cardiovascular disease (CVD) complications. MPO‐mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoprotein functionality. The specificity of guaiacol derivatives toward...

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Veröffentlicht in:ChemMedChem 2020-07, Vol.15 (13), p.1187-1199
Hauptverfasser: Premkumar, Jayaraj, Sampath, Parthasarathy, Sanjay, Rajagopalan, Chandrakala, Aluganti, Rajagopal, Desikan
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Sprache:eng
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Zusammenfassung:Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to cardiovascular disease (CVD) complications. MPO‐mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoprotein functionality. The specificity of guaiacol derivatives toward preventing MPO‐mediated oxidation to limit MPO's harmful effects is unknown. Diligent in silico studies were accomplished for a portfolio of compounds with guaiacol as a building block. The compounds’ activity toward MPO inhibition was also validated. The role of these chemical entities in controlling MPO‐mediated oxidation of lipoproteins (LDL and HDL) was shown to agree with our approach of developing powerful MPO inhibitors. The mechanism of MPO inhibition was demonstrated to be reversible in nature. This study reveals that there is great potential for guaiacol derivatives as therapeutics for CVD by modulating lipid profiles, reducing atherosclerotic plaque burden, and subsequently optimizing cardiovascular functions. Plaque attack: Chemically modified guaiacol derivatives operate well as reversible MPO inhibitors in in vitro and cell line studies. A computation docking study showed that they do this by blocking the MPO active site. Given that these compounds also affect low‐density lipoprotein, they could provide promising therapeutic properties against cardiovascular disease.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000084