Non-naturally Occurring Regio Isomer of Lysophosphatidylserine Exhibits Potent Agonistic Activity toward G Protein-Coupled Receptors

Sho Nakamura, Misa Sayama, Akiharu Uwamizu, Sejin Jung, Masaya Ikubo, Yuko Otani, Kuniyuki Kano, Jumpei Omi, Asuka Inoue, Junken Aoki, Tomohiko Ohwada

Research output: Contribution to journalArticlepeer-review

Abstract

Lysophosphatidylserine (LysoPS), an endogenous ligand of G protein-coupled receptors, consists of l-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages, respectively. An ester linkage of phosphatidylserine can be hydrolyzed at the 1-position or at the 2-position to give 2-acyl lysophospholipid or 1-acyl lysophospholipid, respectively. 2-Acyl lysophospholipid is in nonenzymatic equilibrium with 1-acyl lysophospholipid in vivo. On the other hand, 3-acyl lysophospholipid is not found, at least in mammals, raising the question of whether the reason for this might be that the 3-acyl isomer lacks the biological activities of the other isomers. Here, to test this idea, we designed and synthesized a series of new 3-acyl lysophospholipids. Structure-activity relationship studies of more than 100 "glycol surrogate"derivatives led to the identification of potent and selective agonists for LysoPS receptors GPR34 and P2Y10. Thus, the non-natural 3-acyl compounds are indeed active and appear to be biologically orthogonal with respect to the physiologically relevant 1-and 2-acyl lysophospholipids.

Original languageEnglish
Pages (from-to)9990-10029
Number of pages40
JournalJournal of Medicinal Chemistry
Volume63
Issue number17
DOIs
Publication statusPublished - 2020 Sep 10

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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