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

Kharel Y, Mathews TP, Kennedy AJ, Houck JD, Macdonald TL, Lynch KR. (2011) "A rapid assay for assessment of sphingosine kinase inhibitors and substrates." Anal Biochem. Jan [Epub ahead of print] [PubMed]

East JE, Kennedy AJ, Tomsig JL, De Leon AR, Lynch KR, Macdonald TL. (2010) "Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX)." Bioorg Med Chem Lett. Dec 20(23):7132-6. Epub 2010 Sep 15. [PubMed]

Sefcik LS, Petrie Aronin CE, Awojoodu AO, Shin SJ, Mac Gabhann F, Macdonald TL,Wamhoff BR, Lynch KR, Peirce SM, Botchwey EA. (2010) "Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth." Tissue Eng Part A. Nov [Epub ahead of print] [PubMed]

Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. (2010) "Regulation of learning and memory by meningeal immunity: a key role for IL-4." J Exp Med. May 207:1067-80. Epub 2010 May 3. [PubMed]

Bajwa A, Jo SK, Ye H, Huang L, Dondeti KR, Rosin DL, Haase VH, Macdonald TL,Lynch KR, Okusa MD. (2010) "Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury." J Am Soc Nephrol. 21:955-65. Epub 2010 Mar 25. [PubMed]

Mathews TP, Kennedy AJ, Kharel Y, Kennedy PC, Nicoara O, Sunkara M, Morris AJ,Wamhoff BR, Lynch KR, Macdonald TL. (2010) "Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors." J Med Chem. Apr 53:2766-78. [PubMed]

Ma B, Guckian KM, Lin EY, Lee WC, Scott D, Kumaravel G, Macdonald TL, Lynch KR,Black C, Chollate S, Hahm K, Hetu G, Jin P, Luo Y, Rohde E, Rossomando A,Scannevin R, Wang J, Yang C. (2010) "Stereochemistry-activity relationship of orally active tetralin S1P agonist prodrugs." Bioorg Med Chem Lett. Apr 20:2264-9. Epub 2010 Feb 6. [PubMed]

Petrie Aronin CE, Sefcik LS, Tholpady SS, Tholpady A, Sadik KW, Macdonald TL,Peirce SM, Wamhoff BR, Lynch KR, Ogle RC, Botchwey EA. (2010) "FTY720 promotes local microvascular network formation and regeneration of cranial bone defects." Tissue Eng Part A. 16:1801-9. [PubMed]

Foss FW Jr, Mathews TP, Kharel Y, Kennedy PC, Snyder AH, Davis MD, Lynch KR,Macdonald TL. (2009) "Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs." Bioorg Med Chem. Aug 17(16):6123-36. Epub 2009 Apr 12. [PubMed]

Sim-Selley LJ, Goforth PB, Mba MU, Macdonald TL, Lynch KR, Milstien S, SpiegelS, Satin LS, Welch SP, Selley DE. (2009) "Sphingosine-1-phosphate receptors mediate neuromodulatory functions in the CNS." J Neurochem. 110:1191-202. Epub 2009 May 31. [PubMed]

Tomsig JL, Snyder AH, Berdyshev EV, Skobeleva A, Mataya C, Natarajan V, BrindleyDN, Lynch KR. (2009) "Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo." Biochem J. May 419:611-8. [PubMed]

Rivera-Lopez CM, Tucker AL, Lynch KR. (2008) "Lysophosphatidic acid (LPA) and angiogenesis." Angiogenesis. 11:301-10. Epub 2008 May 27. [PubMed]