OOOROTomohiko Ohwada, Professor, Graduate School of Pharmaceutical Sciences, IntroductionHONH2LysophosphatidylserineUniversity of Tokyo― 276 ―Lysophospholipids are produced from phospholipids that form lipid bilayers through hydrolysis by phospholipases. Lysophospholipids have only one acyl group on the glycerol moiety, and the reduced liposolubility of the side chain allows them to easily leave the membrane and migrate to other membranes, where they act as chemical mediators to transmit various information between cells and organelles. Lysophosphatidylserine (LysoPS) (Figure 1), one of lysophospholipids, has L-serine at its polar head, and one of the hydroxyl groups of glycerol forms an ester bond with a long-chain fatty acid. GPR34 (LPS1) was first reported as a LysoPS receptor, and the orphan GPCRs P2Y10 (LPS2) and GPR174 (LPS3) were newly identified as LysoPS receptors in 2012. Both receptors are highly expressed in immune system tissues, and the involvement of the LysoPS receptor group in immune system diseases has recently been suggested. We illustrate our hypothesis in structural expansion using LysoPS as an example1-15). We focused on the modularity of the LysoPS molecular structure to create a subtype-selective agonist by systematically converting each module (L-serine, glycerol, ester bonds, and fatty acids) of LysoPS and examining the contribution of each module structure to agonist activity against the receptor subtype. The goal was to elucidate the structural requirements for selectivity expression by systematically converting each module (L-serine, glycerol, ester bonds, fatty acids) and examining the contribution of each module structure to agonist activity against receptor subtypes. The hypothesis that activity and selectivity are synergistically enhanced by combining appropriate module structures (mix-and-match) was formulated and tested. Our previous studies demonstrated that the mix-and-match approach was correct and useful in the case of LysoPS.OHPOOOHFigure 1. Structure of Lysophsphatidylserine (LysoPS)(LysoPS)Design and synthesis of subtype-selective and potent agonists toward lysophosphatidic acid receptorsJiankang Zhang2022. 8 ～ 2023. 9
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