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.

Abstract

Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P1) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P1 functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P1 desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P1, could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P1, SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P1 on endothelium without causing receptor desensitization and potently activated protection pathways in human endothelial cells. In a pig model of coronary endothelial damage, SAR247799 improved the microvascular hyperemic response without reducing lymphocyte numbers. Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P1-desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P1 functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P1. These findings demonstrate that sustained S1P1 activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability.

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