A new study, led by the Department of Pharmacology, Toxicology and Therapeutic Chemistry of the University of Barcelona, the Institute of Biomedicine of the University of Barcelona (IBUB) and CIBERDEM, describes the effects of a compound PROTAC (Proteolysis-targeting Chimera) directed against soluble epoxide hydrolase (sEH). This compound, by stimulating the degradation of sEH, causes the activation of the metabolic sensor AMPK, key in energy balance, thus reducing endoplasmic reticulum stress and inflammation in liver cells.
The work, published in the journal Biomedicine & Pharmacotherapy, has been coordinated by professor Manuel Vázquez Carrera, from the aforementioned Department of the Faculty of Pharmacy and Food Sciences, and has had the participation of two other groups from the IBUB led by UB professors Santiago Vázquez and Carles Galdeano, in addition to the CIBERDEM group led by expert Ángela Valverde at the Alberto Sols Institute (UAM-CSIC) and a group from the University of California (United States).
Image of the research team of the Faculty of Pharmacy and Food Sciences, IBUB and CIBERDEM
“In this study we describe a novel PROTAC directed against the sEH enzyme that promotes its degradation in liver cells. The reduction of sEH levels decreases markers of endoplasmic reticulum stress, a process that chronically sustained promotes the development of numerous pathologies such as type 2 diabetes mellitus, as well as markers of inflammation in liver cells,” explains Dr. Vázquez Carrera. The researcher adds that “these changes are due to an activation by PROTAC of AMPK kinase, which is a pharmacological target for the treatment of insulin resistance and type 2 diabetes”.
The study further observed that the reduction in sEH was accompanied by an increase in proteins involved in the insulin signaling pathway.
“While the hydrolase activity of the bifunctional enzyme sEH has been extensively studied and inhibitors are already in clinical trials (for pain, lung disease, insulin resistance, etc.), the phosphatase activity of sEH has been little studied,” the researcher notes.
Recent studies indicate that inactivating phosphatase activity reduces obesity and heart damage. Thus, this work took as its starting point the hypothesis that reducing both sEH hydrolase and phosphatase activity may be more beneficial than solely reducing the former.
“One possible strategy to inhibit both activities is the use of PROTACs, bifunctional compounds that contain an inhibitor of a specific protein, in this case sEH, and which is linked by a linker to a ligand of E3 ligase,” explains Dr. Vázquez Carrera. These compounds, in addition to inhibiting the activity of sEH, also stimulate its degradation in the proteasome, thanks to their binding to E3 ligase. Additionally, this new strategy allows the use of smaller doses of compounds and provides an additional layer of selectivity.
Article reference:
Peyman, Mona; Barroso, Emma; Turcu, Andreea; Estrany, Francesc; Smith, Dáire; Jurado Aguilar, Javier; Rada, Patricia; Morisseau, Christophe; Hammock, Bruce; Valverde, Ángela; Palomer, Xavier; Galdeano, Carles; Vázquez, Santiago; Vázquez-Carrera, Manuel. Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress. Biomed Pharmacother (2023). DOI: 10.1016/j.biopha.2023.115667
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