TY - JOUR
T1 - Non-naturally Occurring Regio Isomer of Lysophosphatidylserine Exhibits Potent Agonistic Activity toward G Protein-Coupled Receptors
AU - Nakamura, Sho
AU - Sayama, Misa
AU - Uwamizu, Akiharu
AU - Jung, Sejin
AU - Ikubo, Masaya
AU - Otani, Yuko
AU - Kano, Kuniyuki
AU - Omi, Jumpei
AU - Inoue, Asuka
AU - Aoki, Junken
AU - Ohwada, Tomohiko
N1 - Funding Information:
This work was supported by JSPS KAKENHI grant numbers JP 26104508 and 16K08157 (Y.O.), 17K08264 (A.I.), and 26293002 (T.O.). M.S. was supported by a Research Fellowship for Young Scientists from JSPS (grant number 16J08059). This research was partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) grant number JP18am0101095, 19ck0106258 (J.A.), the PRIME grant number JP18gm5910013 (A.I.), and the LEAP Grant number JP19gm0010004 (A.I. and J.A.) from Japan Agency for Medical Research and Development (AMED). A part of the computations was performed at the Research Center for Computational Science, Okazaki, Japan.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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 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 nonenzymatic 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 surrogate"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.
AB - 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 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 nonenzymatic 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 surrogate"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.
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U2 - 10.1021/acs.jmedchem.0c01126
DO - 10.1021/acs.jmedchem.0c01126
M3 - Article
C2 - 32787112
AN - SCOPUS:85090869808
VL - 63
SP - 9990
EP - 10029
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 17
ER -