A G protein-biased S1P 1 agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers.

Autor: Poirier B; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Briand V; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Kadereit D; Medicinal Chemistry, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt am Main,, Germany., Schäfer M; Diabetes and Cardiovascular Research, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt am Main, Germany., Wohlfart P; Diabetes and Cardiovascular Research, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt am Main, Germany., Philippo MC; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Caillaud D; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Gouraud L; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Grailhe P; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Bidouard JP; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Trellu M; Drug Metabolism and Pharmacokinetics, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France., Muslin AJ; Diabetes and Cardiovascular Research, Sanofi US Services, 640 Memorial Drive, Cambridge, MA 02139, USA., Janiak P; Diabetes and Cardiovascular Research, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin, France., Parkar AA; Diabetes and Cardiovascular Research, Sanofi US Services, 55 Corporate Drive, Bridgewater, NJ 08807, USA. ashfaqaparkar@gmail.com.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2020 Jun 02; Vol. 13 (634). Date of Electronic Publication: 2020 Jun 02.
DOI: 10.1126/scisignal.aax8050
Abstrakt: Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P 1 ) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P 1 functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P 1 desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P 1, could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P 1 , SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P 1 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 S1P 1 -desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P 1 functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P 1 These findings demonstrate that sustained S1P 1 activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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