Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages.

Autor: Zarrow JE; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Alli-Oluwafuyi AM; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Youwakim CM; Department of Medicine, Division of Cardiology, Vanderbilt University Medical Center. Nashville, Tennessee 37232, United States., Kim K; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States., Jenkins AN; Department of Cell Biology and Physiology, Brigham Young University. Provo, Utah 84602, United States., Suero IC; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Jones MR; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States., Mashhadi Z; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Mackie K; Gill Center and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, United States., Waterson AG; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States., Doran AC; Department of Medicine, Division of Cardiology, Vanderbilt University Medical Center. Nashville, Tennessee 37232, United States., Sulikowski GA; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States., Davies SS; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
Jazyk: angličtina
Zdroj: ACS chemical biology [ACS Chem Biol] 2023 Aug 18; Vol. 18 (8), pp. 1891-1904. Date of Electronic Publication: 2023 Aug 02.
DOI: 10.1021/acschembio.3c00401
Abstrakt: N -Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes N -acyl-phosphatidylethanolamines (NAPEs) to form N -acyl-ethanolamines (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, NAPEPLD expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators ( VU534 and VU533 ) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in Napepld -/- BMDM or after Nape-pld inhibition. Together, these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.
Databáze: MEDLINE
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