G protein-coupled receptors (GPCRs) are also known as 7TM receptors due to their transmembrane domains. they constitute the largest superfamily of receptors for signaling molecules, ligands
Many ligands, including hormones, autacoids, neurotransmitters, and small molecules to large proteins can bind and activate GPCRs.
S1P (Sphingosine-1-phosphate) is a bioactive lysophospholipid metabolite. It is also a second messenger that mediates increases in intracellular calcium levels.
S1P regulates the various responses of various cellular and organ systems, such as cell differentiation, cell migration, cell proliferation, immune response, trafficking of T and B cells, and vascular stability.
Fingolimod (FTY720）is the first-in-class S1P1 agonist of four S1P receptor subtypes. besides, It accelerates drug discovery in this area.
Today, we will introduce another S1P1 agonist.
SEW2871 is a highly selective, orally active S1P1 agonist with an EC50 of 13.8 nM. SEW2871 activates ERK, Akt, and Rac signaling pathways and induces S1P1 internalization and recycling.
Crohn’s disease (CD) is a major form of inflammatory bowel disease (IBD). And, colon length is an indication of inflammation and fibrosis in CD.
In IL-10–/– and wild-type (WT) mice. SEW2871 increases the length of the colon in IL-10–/– mice. Moreover, H& E-stained colonic specimens show that sew reduces inflammatory infiltration and disruption in crypt architecture.
SEW2871 can block T cell egress to peripheral tissues to exhibits its immunomodulatory effectiveness. the percentage of CD4+CD45+ T cells in the blood in IL-10–/– controls is higher than WT mice. However, SEW2871 can significantly decrease the percentage of CD4+CD45+ T cells in the blood.
Nextly, changes in the production of cytokines and gene expression for inflammatory cytokine is analyzed. SEW2871 lowers TNF-α, IFN-γ, IL-1β and IL-17A mRNA levels in WT mice. In addition, IL-12p40 expression exists no difference between control and SEW2871 groups.
Lastly, SEW2871 reduces p-STAT-3 expression significantly in lymphocytes isolated from IL-10–/– mouse colon LP. As well as, it does not affect the levels of total STAT-3 proteins.
In conclusion, SEW2871 effectively ameliorates colitis in IL-10–/– mice, this molecule might be a candidate for the treatment of patients with CD.
Park SJ, et al. Biomol Ther (Seoul). 2017 Jan 1;25(1):80-90.
Dong J, et al. Clin Exp Immunol. 2014 Jul;177(1):94-101.