Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions.

Molecular Pharmacology
Pedro J Gonzalez-CabreraHugh Rosen

Abstract

Strong evidence exists for interactions of zwitterionic phosphate and amine groups in sphingosine-1 phosphate (S1P) to conserved Arg and Glu residues present at the extracellular face of the third transmembrane domain of S1P receptors. The contribution of Arg(120) and Glu(121) for high-affinity ligand-receptor interactions is essential, because single-point R(120)A or E(121)A S1P(1) mutants neither bind S1P nor transduce S1P function. Because S1P receptors are therapeutically interesting, identifying potent selective agonists with different binding modes and in vivo efficacy is of pharmacological importance. Here we describe a modestly water-soluble highly selective S1P(1) agonist [2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino) ethanol (CYM-5442)] that does not require Arg(120) or Glu(121) residues for activating S1P(1)-dependent p42/p44 mitogen-activated protein kinase phosphorylation, which defines a new hydrophobic pocket in S1P(1). CYM-5442 is a full agonist in vitro for S1P(1) internalization, phosphorylation, and ubiquitination. It is noteworthy that CYM-5442 was a full agonist for induction and maintenance of S1P(1)-dependent blood lymphopenia, decreasing B lymphocytes by 65% and T ly...Continue Reading

References

Apr 10, 1999·Molecular Biology of the Cell·C H LiuT Hla
Sep 13, 2000·The Journal of Biological Chemistry·A L ParrillG Tigyi
Sep 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Hugh RosenMichael G McHeyzer-Williams
Jul 7, 2005·Nature Reviews. Immunology·Hugh Rosen, Edward J Goetzl
Nov 23, 2006·The Journal of Biological Chemistry·Yuko FujiwaraGabor Tigyi
Jan 16, 2007·The Journal of Biological Chemistry·Pedro J Gonzalez-CabreraHugh Rosen
Feb 6, 2007·Trends in Immunology·Hugh RosenPedro J Gonzalez-Cabrera
Nov 21, 2007·Nature Immunology·Susan R Schwab, Jason G Cyster
Jul 11, 2008·Immunological Reviews·Hugh RosenM Germana Sanna
Aug 6, 2008·Journal of the Neurological Sciences·Veronique E MironJack P Antel
Aug 8, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Michael A Weinreich, Kristin A Hogquist

❮ Previous
Next ❯

Citations

Jun 15, 2013·Trends in Pharmacological Sciences·Catherine O'Sullivan, Kumlesh K Dev
Sep 14, 2012·ACS Chemical Biology·Euijung JoHugh Rosen
Aug 21, 2013·Nature Reviews. Drug Discovery·Gregory T KunkelSarah Spiegel
Jan 23, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jia-Jun LiaoEdward J Goetzl
Mar 20, 2013·Current Opinion in Hematology·Linda J Bendall, Jordan Basnett
Feb 22, 2012·Science·Michael A HansonRaymond C Stevens
Feb 24, 2009·Annual Review of Biochemistry·Hugh RosenSteven Brown
Jan 19, 2010·American Journal of Respiratory Cell and Molecular Biology·Barry S SheaAndrew M Tager
May 11, 2011·The Journal of Clinical Investigation·Myat Lin OoTimothy Hla
Apr 22, 2014·Trends in Pharmacological Sciences·Julia K ArchboldMatthew J Sweet
Mar 27, 2013·Annual Review of Biochemistry·Hugh RosenMichael B A Oldstone
Mar 30, 2011·Nature Chemical Biology·Stuart M CahalanHugh Rosen
Apr 30, 2015·Critical Reviews in Biochemistry and Molecular Biology·Michael J Pulkoski-GrossLina M Obeid
Apr 26, 2011·Trends in Molecular Medicine·Susan Pyne, Nigel J Pyne
Nov 26, 2015·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Yaling LiTao Ren
Feb 12, 2011·British Journal of Pharmacology·Mirjam SchuchardtMarkus van der Giet
Mar 8, 2014·British Journal of Pharmacology·Yasuyuki KiharaJerold Chun
Jun 6, 2015·Cell·Stuart L SchreiberUNKNOWN NIH Molecular Libraries Project Team
Jan 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Hjalmar R BoumaRobert H Henning
Sep 14, 2012·Biochemical Pharmacology·Sandra P WelchDana E Selley
Aug 3, 2016·Medicinal Research Reviews·Dominik Vogt, Holger Stark
Oct 4, 2017·The Journal of Endocrinology·Stephan WerthWalter Raasch
Jul 28, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Chiara TobiaMarco Presta
May 14, 2016·Stroke; a Journal of Cerebral Circulation·Na SunFu-Dong Shi
Mar 21, 2009·Nature Reviews. Drug Discovery·David Marsolais, Hugh Rosen
May 14, 2017·The Journal of Pharmacology and Experimental Therapeutics·Alice MarinoRoberto Levi

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.