Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are phospholipid growth factors involved in signaling pathways that regulate vascular remodeling, immune cell trafficking and development of neuronal and cardiovascular systems. LPA can initiate the early steps of neointima formation, demonstrating the importance of additional studies on its role in cardiovascular disease. The proposed studies outline varied approaches that address a single fundamental question. Namely, what structural characteristics confer selective agonist and/or antagonist activity at individual phospholipid growth factor receptors? This question is important because this receptor family is involved in diverse biological responses related to cardiovascular disease and carcinogenesis that remain incompletely characterized due to overlapping expression patterns and a lack of receptor-selective pharmacological probes. Our prior structural characterization of both agonist and antagonist binding to these receptors uniquely positions us to answer this fundamental question and provide much-needed research tools. The question will be addressed through the following specific aims: 1. Validate the LPA GPCR antagonist binding site using a model-driven mutagenesis strategy. 2. Determine the NMR structure of the computationally-designed extracellular loop mimetic peptides and evaluate their applicability to screen for antagonist interactions. 3. Develop predictive computational models (QSAR and pharmacophore) of agonist/antagonist action at LPA GPCR and PPARgamma receptors and apply them in the discovery of novel agonist and antagonist lead compound architectures. This research has the potential to reveal new leads for the development of therapeutic compounds for the prevention and treatment of cardiovascular disease. Cardiovascular disease accounted for 1 in every 2.6 deaths in the United States in 2001 and the World Health Organization indicates that 16.7 million annual deaths occur globally due to cardiovascular disease. Additional therapeutic strategies for this disease are critically needed and of broad benefit to public health. The LPA receptors additional stimulate cancer cell motility. Agents that block activation of these receptors may therefore inhibit the invasiveness and metastasis of tumors, serving as important chemotherapeutic leads. This research can therefore lead to new treatments for cardiovascular disease and cancer. ? ? ?
| Parrill, Abby L; Tigyi, Gabor (2013) Integrating the puzzle pieces: the current atomistic picture of phospholipid-G protein coupled receptor interactions. Biochim Biophys Acta 1831:2-12 |
| Parrill, Abby L; Lima, Santiago; Spiegel, Sarah (2012) Structure of the first sphingosine 1-phosphate receptor. Sci Signal 5:pe23 |
| Parrill, Abby L (2012) Comparative modeling of lipid receptors. Methods Mol Biol 914:207-18 |
| Parrill, Abby L (2011) Lysophosphatidic acid receptor agonists and antagonists (WO2010051053). Expert Opin Ther Pat 21:281-6 |
| Mize, Catrina D; Abbott, Ashley M; Gacasan, Samantha B et al. (2011) Ligand-based autotaxin pharmacophore models reflect structure-based docking results. J Mol Graph Model 31:76-86 |
| Tsukahara, Tamotsu; Tsukahara, Ryoko; Fujiwara, Yuko et al. (2010) Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. Mol Cell 39:421-32 |
| Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong et al. (2010) 2D binary QSAR modeling of LPA3 receptor antagonism. J Mol Graph Model 28:828-33 |
| Parrill, Abby L; Baker, Daniel L (2010) Autotaxin inhibitors: a perspective on initial medicinal chemistry efforts. Expert Opin Ther Pat 20:1619-25 |
| Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong et al. (2009) Structure-based drug design identifies novel LPA3 antagonists. Bioorg Med Chem 17:7457-64 |
| North, E Jeffrey; Osborne, Daniel A; Bridson, Peter K et al. (2009) Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs. Bioorg Med Chem 17:3433-42 |
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