A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P1 agonists. Issue 10 (4th September 2020)

• Record Type: Journal Article
• Authors: Grailhe, Patrick; Boutarfa‐Madec, Asma; Beauverger, Philippe; Janiak, Philip; Parkar, Ashfaq A.
• Is Part Of: FEBS open bio. Volume 10:Issue 10(2020)
• Page Start: 2010
• Page End: 2020
• Publication Date: 2020-09-04
• Subjects: desensitization -- endothelium -- impedance -- S1P1 -- SAR247799 -- siponimod; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12951
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : Sphingosine‐1 phosphate receptor‐1 (S1P1 ) activation maintains endothelial barrier integrity, whereas S1P1 desensitization induces peripheral blood lymphopenia. The latter is exploited in the approval and/or late‐stage development of receptor‐desensitizing agents targeting the S1P1 receptor in multiple sclerosis, such as siponimod, ozanimod, and ponesimod. SAR247799 is a recently described G protein‐biased S1P1 agonist that activates S1P1 without desensitization and thus has endothelial‐protective properties in patients without reducing lymphocytes. As SAR247799 demonstrated endothelial‐protective effects at sub‐lymphocyte‐reducing doses, the possibility exists that other S1P1 modulators could also exhibit endothelial‐protective properties at lower doses. To explore this possibility, we sought to quantitatively compare the biased properties of SAR247799 with the most advanced clinical molecules targeting S1P1 . In this study, we define the β‐arrestin pathway component of the impedance profile following S1P1 activation in a human umbilical vein endothelial cell line (HUVEC) and report quantitative indices of the S1P1 activation‐to‐desensitization ratio of various clinical molecules. In a label‐free impedance assay assessing endothelial barrier integrity and disruption, the mean estimates (95% confidence interval) of the activation‐to‐desensitization ratios of SAR247799, ponesimod, ozanimod, and siponimod were 114 (91.1–143), 7.66 (3.41–17.2), 6.35 (3.21–12.5), and 0.170 (0.0523–0.555), respectively. Thus, we show that SAR247799 is the most G protein‐biased S1P1 agonist currently characterized. This rank order of bias among the most clinically advanced S1P1 modulators provides a new perspective on the relative potential of these clinical molecules for improving endothelial function in patients in relation to their lymphocyte‐reducing (desensitization) properties. Abstract : S1P1 activation maintains endothelial barrier integrity, whereas its desensitization induces lymphopenia. SAR247799, a new G protein‐biased S1P1 agonist, was compared to clinical stage S1P1 ‐desensitizing compounds using a label‐free impedance assay assessing endothelial barrier integrity. SAR247799 had the highest activation‐to‐desensitization ratio (114), compared to ponesimod (7.66), ozanimod (6.35), and siponimod (0.170) and thus demonstrated the best ability to cause sustained S1P1 activation.