Research ArticlePharmacology

A G protein–biased S1P1 agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers

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Science Signaling  02 Jun 2020:
Vol. 13, Issue 634, eaax8050
DOI: 10.1126/scisignal.aax8050

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More targeted endothelial protection

The bioactive lipid S1P binds to a family of widely distributed GPCRs. Agonists of the S1P receptor S1P1 trigger β-arrestin–dependent desensitization and, consequently, lymphocyte egress, making them clinically useful in the treatment of autoimmune diseases. However, lymphopenia would be an undesirable side effect when activating S1P1 in other cell types. Poirier et al. identified an S1P1 agonist, SAR247799, which preferentially activated G protein signaling. Ischemia/reperfusion injury induces endothelial damage, and SAR247799 maintained endothelial function and reduced tissue damage caused by this type of injury in two different animal models. Thus, the characteristics of SAR247799 demonstrate that it is possible to target S1P1 in the endothelium without compromising immune responses.

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