University of Virginia Health System

The over-arching goal of this laboratory’s research is to understand better the biology of lysophospholipid signaling, particularly in the context of pathologies. The central strategy remains the development of tools (mostly small molecules) with which to probe lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) biology. We complement this chemical biology approach with mouse genetics. The new chemical entities developed recently include a LPA3 receptor antagonist, a LPA1/LPA3 receptor selective antagonist and inhibitors of the LPA-producing phospholipase, autotaxin. Further, we have identified S1P receptor agonists (including pro-drugs) and a S1P1/S1P3 receptor antagonist. The syntheses of these molecules were done in the laboratory of our long term collaborator, Professor Timothy L. Macdonald (UVA Department of Chemistry).

Using the latest generation of compounds, we found that LPA receptor antagonists are anti-angiogenic in the chicken chorioallantoic membrane (CAM) assay. These antagonists are being taken forward to angiogenesis assays in rodents. The Macdonald Lab provided us recently with a high affinity LPA1 receptor antagonist that is stable metabolically. In addition to the aforementioned angiogenesis assays, this compound is being tested currently in several neoplasia models including melanoma, ovarian and breast cancer. We are using an invertebrate (brown recluse spider) lysophospholipase D to learn the effects of local LPA generation on angiogenesis and tumor development in mice. The LPA receptor types implicated in biologic processes by our small molecules are being tested also using LPA1 and LPA3 receptor ‘knock-out’ mice.

Among our S1P receptor compounds, we are concentrating on S1P receptor agonist pro-drugs and S1P1 receptor antagonists. S1P1 receptor agonists block lymphocyte egress from lymph nodes and thereby modulate the immune system. The lead drug in this class, FTY720 (fingolimod), is efficacious in autoimmune disease models. We used structure activity relationships of our set of sphingosine analogs and our sphingosine kinase 2 (SPHK2) null mice to document recently that our S1P prodrugs, like FTY720, are activated by SPHK2 catalyzed phosphorylation. We are particularly interested in using our S1P agonist compounds to interdict the development of type 1 diabetes and treat its complications such as atherosclerosis and neuropathic pain. We are taking our lead S1P1 receptor antagonist forward into cancer and angiogenesis models.

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