Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor

Chem Commun (Camb). 2018 Nov 8;54(90):12758-12761. doi: 10.1039/c8cc05595e.

Abstract

Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P1) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P1.

MeSH terms

  • Animals
  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / metabolism
  • Salicylates / chemical synthesis
  • Salicylates / chemistry
  • Salicylates / pharmacology*
  • Sphingolipids / agonists*
  • Sphingolipids / metabolism
  • Structure-Activity Relationship
  • Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors*
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Biological Products
  • Enzyme Inhibitors
  • Receptors, Lysosphingolipid
  • Salicylates
  • Sphingolipids
  • ginkgolic acid
  • Transferases (Other Substituted Phosphate Groups)
  • phosphatidylcholine-ceramide phosphocholine transferase