Sho Nakamura, Misa Sayama, Akiharu Uwamizu
Jul 28, 2020
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0
Influential Citations
9
Citations
Quality indicators
Journal
Journal of medicinal chemistry
Abstract
Lysophosphatidylserine (LysoPS), an endogenous ligand of G protein-coupled receptors, consists of L-serine, glycerol and fatty acid moieties connected by phosphodiester and ester linkages, respectively. An ester linkage of phosphatidylserine (PS) can be hydrolyzed at the 1-position or at the 2-position, to give 2-acyl lysophospholipid or 1-acyl lysophospholipid, respectively. 2-Acyl lysophospholipid is in non-enzymatic equilibrium with 1-acyl lysophospholipid in vivo. On the other hand, 3-acyl lysophospholipid is not found, at least in mammals, raising the question of whether the reason for this might be that the 3-acyl isomer lacks the biological activities of the other isomers. Here, to test this idea, we designed and synthesized a series of new 3-acyl lysophospholipids. Structure-activity relationship studies of more than 100 "glycol surrogates" derivatives led to the identification of potent and selective agonists for LysoPS receptors GPR34 and P2Y10. Thus, the non-natural 3-acyl compounds are indeed active, and appear to be biologically orthogonal with respect to the physiologically relevant 1- and 2-acyl lysophospholipids.