Druggable Lysophospholipid Signaling Pathways
Lysophosphatidic acid (LPA) has major roles as a bioactive signaling molecule, with multiple physiological and pathological roles being described in almost every major organ system. In this review we discuss LPA signaling pathways as emerging drug targets
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Druggable Lysophospholipid Signaling Pathways Keisuke Yanagida and William J. Valentine
Abstract
Lysophosphatidic acid (LPA) has major roles as a bioactive signaling molecule, with multiple physiological and pathological roles being described in almost every major organ system. In this review we discuss LPA signaling pathways as emerging drug targets for multiple conditions relevant to human health and disease. LPA signals through the six G protein- coupled receptors LPA1-6, and several of these receptors along with the LPA-producing enzyme including autotaxin (ATX) are now established as therapeutic targets with potential to treat various human diseases as exemplified by several LPA signaling targeting compounds now in clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. Several crystal structures of LPA receptors and ATX have been solved, which will accelerate development of highly selective and effective LPA signaling targeting compounds. K. Yanagida (*) Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan e-mail: [email protected] W. J. Valentine Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan Department of Molecular Therapy, National Center of Neurology and Psychiatry, Tokyo, Japan e-mail: [email protected]
We also review additional bioactive lysophospholipid (LPL) signaling molecules including lysophosphatidylserine and lysophosphatidylinositol, which represent the next wave of LPL druggable targets. An emerging theme in bioactive LPL signaling is that where the ligand is produced and how it is delivered to the cognate receptor are critical determinants of the biological responses. We will also discuss how connecting the production and function of bioactive LPLs will identify new therapeutic strategies to effectively target LPL signaling pathways. Keywords
GPCR · LysoPS · LPI · Lysophosphatidylglucoside · Lysophosphatidylcholine · GPR55 · GPR34 · P2Y10 · GPR174
7.1
Introduction
Lysophospholipids (LPLs), glycerophospholipids with just one fatty chain, include lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (lysoPS) and lysophosphatidylinositol (LPI) (Fig. 7.1). LPLs were recognized in the early 1900s as cytolytic substances derived from
© Springer Nature Switzerland AG 2020 Y. Kihara (ed.), Druggable Lipid Signaling Pathways, Advances in Experimental Medicine and Biology 1274, https://doi.org/10.1007/978-3-030-50621-6_7
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K. Yanagida and W. J. Valentine
138 O
HO CH2
C O CH2 HO CH
O C O CH O CH2 O P OH
O
CH2 O P OH
1-Palmitoyl-LPA (1-acyl-LPA)
O-
O-
2-Arachidonoyl-LPA (2-acyl-LPA) HO CH2 O C O CH O CH2 O P O O-
NH2 COOH
2-Arachidonoyl-lysoPS O O
CH2 O P O
1-Stearoyl-LysoPtdGlc
O-
CH2
HO HO
HO CH
HO
HO HO HO HO HO
O-
2-Arachidonoyl-LPI
C O CH2 O
O C O CH O CH2 O P O
HO
HO CH2
Fig. 7.1 Chemical structures of LPL ligands Representative structures of LPLs including LPA, lysoPS, LPI and Lyso
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