2. Academic Validation
  3. Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions

Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions

  • Cell Chem Biol. 2019 Feb 21;26(2):244-254.e4. doi: 10.1016/j.chembiol.2018.10.023.
Nan Chiang 1,  Elena Barnaeva 2,  Xin Hu 2,  Juan Marugan 2,  Noel Southall 2,  Marc Ferrer 3,  Charles N Serhan 4
Affiliations

Affiliations

  • 1 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road BTM 3-016, Boston, MA 02115, USA.
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  • 3 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA. Electronic address: marc.ferrer@nih.gov.
  • 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road BTM 3-016, Boston, MA 02115, USA. Electronic address: cserhan@bwh.harvard.edu.
PMID: 30554914 DOI: 10.1016/j.chembiol.2018.10.023
Abstract

Resolution of acute inflammation is governed, in part, by specialized pro-resolving mediators, including lipoxins, resolvins, protectins, and maresins. Among them, resolvin D1 (RvD1) exhibits potent pro-resolving functions via activating human resolvin D1 receptor (DRV1/GPR32). RvD1 is a complex molecule that requires challenging organic synthesis, diminishing its potential as a therapeutic. Therefore, we implemented a high-throughput screening of small-molecule libraries and identified several chemotypes that activated recombinant DRV1, represented by NCGC00120943 (C1A), NCGC00135472 (C2A), pMPPF, and pMPPI. These chemotypes also elicited rapid impedance changes in cells overexpressing recombinant DRV1. With human macrophages, they each stimulated phagocytosis of serum-treated zymosan at concentrations comparable with that of RvD1, the endogenous DRV1 ligand. In addition, macrophage phagocytosis of live E. coli was significantly increased by these chemotypes in DRV1-transfected macrophages, compared with mock-transfected cells. Taken together, these chemotypes identified by unbiased screens act as RvD1 mimetics, exhibiting pro-resolving functions via interacting with human DRV1.

Keywords

G-protein-coupled receptor; GPR32; HTS; chemotype; inflammation; macrophage; phagocytosis; resolution; resolution agonist.

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