Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein–coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.
Rationale Vascular permeability is a hallmark of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury pathobiology; however, the mechanisms underlying this vascular dysregulation remain unclear, thereby impairing the development of desperately needed effective therapeutics. We have shown that sphingosine-1-phosphate (S1P) and 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720) analogues are useful tools for exploring vascular barrier regulation mechanisms. Objective To experimentally define the effects of FTY720 regioisomers on lung endothelial cell barrier regulation. Methods Specific barrier-regulatory receptor and kinase inhibitors were utilized to probe signaling mechanisms involved in FTY720 regioisomer-mediated human lung endothelial cell barrier responses (trans-endothelial electrical resistance, TER). Docking simulations with the S1P1 receptor were performed to further evaluate FTY720 regioisomer signaling. Results FTY720 regioisomers produced potent endothelial cell barrier disruption reflected by declines in TER alterations. Pharmacologic inhibition of Gi-coupled S1P receptors (S1P1, S1P2, S1P3) failed to alter FTY720 regioisomer-mediated barrier disruption; findings that were corroborated by docking simulations demonstrating FTY720 regiosomers were repelled from S1P1 docking, in contrast to strong S1P1 binding elicited by S1P. Inhibition of either the barrier-disrupting PAR-1 receptor, the VEGF receptor, Rho-kinase, MAPK, NFkB, or PI3K failed to alter FTY720 regioisomer-induced endothelial cell barrier disruption. While FTY720 regioisomers significantly increased protein phosphatase 2 (PP2A) activity, PP2A inhibitors failed to alter FTY720 regioisomer-induced endothelial cell barrier disruption. Conclusions Together, these results imply a vexing model of pulmonary vascular barrier dysregulation in response to FTY720-related compounds and highlight the need for further insights into mechanisms of vascular integrity required to promote the development of novel therapeutic tools to prevent or reverse the pulmonary vascular leak central to ARDS outcomes.
The sphingosine-1-phosphate receptor 1 (S1P 1), originally the endothelial differentiation gene 1 receptor (EDG-1), is one of five G protein-coupled receptors (GPCRs) S1P 1−5 that bind to and are activated by sphingosine-1-phosphate (S1P). The lipid S1P is an intermediate in sphingolipid homeostasis, and S1P 1 is a major medical target for immune system modulation; agonism of the receptor produces a myriad of biological responses, including endothelial cell barrier integrity, chemotaxis, lymphocyte trafficking/targeting, angiogenesis, as well as regulation of the cardiovascular system. Use of in silico docking simulations on the crystal structure of S1P 1 allows for pinpointing the residues within the receptor's active site that actively contribute to the binding of S1P, and point to how these specific interactions can be exploited to design more effective synthetic analogs to specifically target S1P 1 in the presence of the closely related receptors S1P 2 , S1P 3 , S1P 4 , and S1P 5. We examined the binding properties of the endogenous substrate as well as a selection of synthetic sphingosine-derived S1P 1 modulators of S1P 1 with in silico docking simulations using the software package Molecular Operating Environment R (MOE R). The modeling studies reveal the relevance of phosphorylation, i.e., the presence of a phosphate or phosphonate moiety within the substrate for successful binding to occur, and indicate which residues are responsible for S1P 1 binding of the most prominent sphingosine-1-phosphate receptor (S1PR) modulators, including fingolimod and its structural relatives. Furthermore, trends in steric preferences as for the binding of enantiomers to S1P 1 could be observed, facilitating future design of receptor-specific substrates to precisely target the active site of S1P 1 .
This modular, open-framework capstone course delves deeply into the synthesis, separation, and characterization of chiral molecules while teaching critical thinking and writing skills in a research-like setting within a fertile area for discovery. This course has evolved over 30 years and has been in its present form for 5 years at the time of this writing. The studies described can be easily integrated into a curriculum with other related disciplines, including medicinal, synthetic, analytical, and physical chemistry. The first procedure introduces Pasteur's classic resolution of (±)-α-phenylethylamine by cocrystallization with enantio-pure Dtartaric acid. The enantiomerically enriched α-phenylethylamine is then characterized using three different methods: polarimetry to measure [α] D , high-performance liquid chromatography (HPLC) with a chiral column to determine the enantiomeric ratio (e.r.), and by proton nuclear magnetic resonance ( 1 H NMR) using a chiral shift reagent. In the second experiment, students carry out a stereoselective alkylation of a glycine Schiff base using a cinchonine-derived phase-transfer catalyst and methods first developed by O'Donnell and expanded on by many other chemists around the world. The students are encouraged to read the primary literature and design their own experiments with the guidance of the instructors and graduate student teaching assistants (TAs). In our course, the first experiment is described as a communication and the alkylation experiment is reported in the format of a full paper.
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