Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are structurally-related molecules that mammals use as extracellular messengers. Acting via a set of at least eight G-protein-coupled receptors, these molecules evoke a wide variety of responses from cells and tissues. We investigate the LPA and S1P using chemical biology primarily and mouse genetics secondarily. In exploring the structure-activity relationships of LPA and S1P compounds, we collaborate closely with Professor T.L. Macdonald's laboratory in the Department of Chemistry at UVA. Of particular interest to us is the investigational drug, FTY720, which is an agonist at multiple S1P receptor types and modulates immune system activity by interfering with lymphocyte trafficking. We generated sphingosine kinase type 2 null mice and found that this enzyme isotype is necessary for the activation of this drug. We have developed a set of receptor type-selective S1P agonists to understand better the efficacy (and toxicities) of FTY720. In the course of these studies we have discovered S1P antagonist compounds as well as inhibitors of sphingosine kinase. Regarding LPA, we have developed receptor antagonists and inhibitors of LPA synthetic enzymes. One LPA receptor antagonist that is potent and stable in vivo is effective in several mouse oncology models. With various collaborators, we deploy our S1P and LPA molecules in a variety of animal models including ischemia-reperfusion injury, atherosclerosis, vascular injury, neuropathic pain, solid tumors, metastasis and autoimmune diseases. Type 1 diabetes and angiogenesis are particular areas of focus. The research is supported by research grants from the National Institutes of Health, foundations and the pharmaceutical industry and income from licensing activities.

Selected References

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, PrieschlE, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR. (2002) "The immune modulator FTY720 targets sphingosine 1-phosphate receptors." J Biol Chem. Jun 277(24):21453-7. Epub 2002 Apr 19. [PubMed]

Okusa MD, Ye H, Huang L, Sigismund L, Macdonald T, Lynch KR. (2003) "Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury." Am J Physiol Renal Physiol. 285:F565-74. Epub 2003 May 27. [PubMed]

Davis MD, Clemens JJ, Macdonald TL, Lynch KR. (2005) "Sphingosine 1-phosphate analogs as receptor antagonists." J Biol Chem. Mar 280(11):9833-41. Epub 2004 Dec 8. [PubMed]

Lee S, Lynch KR. (2005) "Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA)." Biochem J. Oct 391(Pt 2):317-23. [PubMed]

Kharel Y, Lee S, Snyder AH, Sheasley-O'neill SL, Morris MA, Setiady Y, Zhu R,Zigler MA, Burcin TL, Ley K, Tung KS, Engelhard VH, Macdonald TL, Pearson-WhiteS, Lynch KR. (2005) "Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720." J Biol Chem. Nov 280(44):36865-72. Epub 2005 Aug 10. [PubMed]

Foss FW Jr, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL. (2007) "Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists." Bioorg Med Chem. Jan 15:663-77. Epub 2006 Nov 1. [PubMed]

Zhu R, Snyder AH, Kharel Y, Schaffter L, Sun Q, Kennedy PC, Lynch KR, MacdonaldTL. (2007) "Asymmetric synthesis of conformationally constrained fingolimod analogues-discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist." J Med Chem. Dec 50(25):6428-35. Epub 2007 Nov 10. [PubMed]