Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
The over-arching goal of our research is to understand better the biology of sphingosine 1-phosphate (S1P), particularly in the context of disease. S1P is a pleiotropic extracellular lipid that is implicated in control of lymphocyte trafficking, heart rate and vascular leakage. Recently, a S1P receptor agonist pro-drug, fingolimod, was approved as immune system modulator in the treatment of multiple sclerosis.
Our central strategy remains the development of tools (mostly small molecules) with which to probe S1P biology. We complement our chemical biology approach with mouse genetics. The new chemical entities that we have developed including S1P receptor agonists and antagonists. The synthesis of these molecules was accomplished in the laboratory of our long term collaborator, Professor Timothy L. Macdonald (Univ. VA Chemistry).
The current focus of our work is to develop reagents to explore the mechanisms whereby S1P plasma levels (300 nM) are maintained and consequences of manipulating vascular S1P tone. To this end, we have developed potent inhibitors of the S1P synthetic enzyme, sphingosine kinase (SphK). Administration of our inhibitors to mice and rats revealed that circulating S1P decreased rapidly (minutes) in response to SphK1 inhibition. We have also developed SphK2-selective inhibitors in collaboration with Professor Webster L. Santos (VA Tech Chemistry). Among our current challenges is modifying our SphK inhibitors to make them more persistent in vivo while retaining potency and selectivity. Such molecules will allow testing of the hypothesis that interdicting S1P synthesis at the level of SphK will influence the course of disease in models of inflammation and cancer.
Our work is funded by the National Institutes of Health (NIGMS, NICHD), a private foundation and the pharmaceutical industry.
Kharel, Y, TP Mathews, AM Gellett, JL Tomsig, PC Kennedy, ML Moyer, TL Macdonald and KR Lynch. Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. Biochemical Journal (August 18, 2011) doi:10.1042/BJ20110817 PMID: 21848514 PMCID: Journal-in-Progress
Kennedy, PC, R Zhu, T Huang, JL Tomsig, TP Mathews, M David, O Peyruchaud, TL Macdonald and KR Lynch. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacology & Experimental Therapeutics 338, 879-889 PMID: 21632869 PMCID: Journal-in-Progress
Kennedy, AJ, TP Mathews, Y Kharel, SD Field, ML Moyer, JE East, JD Houck, KR Lynch and TL Macdonald. Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells. J Medicinal Chemistry 54, 3524-3548 (2011) PMID: 21495716 NIHMSID: NIHMS293508 PMCID: PMC3119570
Kharel, Y, TP Mathews, AJ Kennedy, TL Macdonald and KR Lynch. A rapid assay for assessment of sphingosine kinase inhibitors and substrates. Analytical Biochemistry 411, 230-235 (2011) PMID: 21216217 NIHMSID: NIHMS271325 PMCID: PMC3049835
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