S1P1-selective in vivo-active agonists from high-throughput screening

Off-the-shelf chemical probes of receptor interactions, signaling, and fate

Euijung Jo, M. Germana Sanna, Pedro J. Gonzalez-Cabrera, Shobha Thangada, Gabor Tigyi, Daniel A. Osborne, Timothy Hla, Abby L. Parrill, Hugh Rosen

Research output: Contribution to journalArticle

198 Citations (Scopus)

Abstract

The essential role of the sphingosine 1-phosphate (S1P) receptor S1P 1 in regulating lymphocyte trafficking was demonstrated with the S1P1-selective nanomolar agonist, SEW2871. Despite its lack of charged headgroup, the tetraaromatic compound SEW2871 binds and activates S1P1 through a combination of hydrophobic and ion-dipole interactions. Both S1P and SEW2871 activated ERK, Akt, and Rac signaling pathways and induced S1P1 internalization and recycling, unlike FTY720-phosphate, which induces receptor degradation. Agonism with receptor recycling is sufficient for alteration of lymphocyte trafficking by S1P and SEW2871. S1P1 modeling and mutagenesis studies revealed that residues binding the S1P head-group are required for kinase activation by both S1P and SEW2871. Therefore, SEW2871 recapitulates the action of S1P in all the signaling pathways examined and overlaps in interactions with key headgroup binding receptor residues, presumably replacing salt-bridge interactions with ion-dipole interactions.

Original languageEnglish (US)
Pages (from-to)703-715
Number of pages13
JournalChemistry and Biology
Volume12
Issue number6
DOIs
StatePublished - Jan 1 2005

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Screening
Throughput
Lymphocytes
Recycling
Lysosphingolipid Receptors
Ions
Mutagenesis
SEW2871
sphingosine 1-phosphate
Phosphotransferases
Salts
Chemical activation
Degradation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

S1P1-selective in vivo-active agonists from high-throughput screening : Off-the-shelf chemical probes of receptor interactions, signaling, and fate. / Jo, Euijung; Sanna, M. Germana; Gonzalez-Cabrera, Pedro J.; Thangada, Shobha; Tigyi, Gabor; Osborne, Daniel A.; Hla, Timothy; Parrill, Abby L.; Rosen, Hugh.

In: Chemistry and Biology, Vol. 12, No. 6, 01.01.2005, p. 703-715.

Research output: Contribution to journalArticle

Jo, Euijung ; Sanna, M. Germana ; Gonzalez-Cabrera, Pedro J. ; Thangada, Shobha ; Tigyi, Gabor ; Osborne, Daniel A. ; Hla, Timothy ; Parrill, Abby L. ; Rosen, Hugh. / S1P1-selective in vivo-active agonists from high-throughput screening : Off-the-shelf chemical probes of receptor interactions, signaling, and fate. In: Chemistry and Biology. 2005 ; Vol. 12, No. 6. pp. 703-715.
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