13 research outputs found
Synthesis and Evaluation of Lysophosphatidylserine Analogues as Inducers of Mast Cell Degranulation. Potent Activities of Lysophosphatidylthreonine and Its 2-Deoxy Derivative
Expression of Phosphatidylserine-Specific Phospholipase A1 mRNA in Human THP-1-Derived Macrophages
Probing the Hydrophobic Binding Pocket of G‑Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS<sub>1</sub> by Docking-Aided Structure–Activity Analysis
The
ligands of certain G-protein-coupled receptors (GPCRs) have
been identified as endogenous lipids, such as lysophosphatidylserine
(LysoPS). Here, we analyzed the molecular basis of the structure–activity
relationship of ligands of GPR34, one of the LysoPS receptor subtypes,
focusing on recognition of the long-chain fatty acid moiety by the
hydrophobic pocket. By introducing benzene ring(s) into the fatty
acid moiety of 2-<i>deoxy</i>-LysoPS, we explored the binding
site’s preference for the hydrophobic shape. A tribenzene-containing
fatty acid surrogate with modifications of the terminal aromatic moiety
showed potent agonistic activity toward GPR34. Computational docking
of these derivatives with a homology modeling/molecular dynamics-based
virtual binding site of GPR34 indicated that a kink in the benzene-based
lipid surrogates matches the L-shaped hydrophobic pocket of GPR34.
A tetrabenzene-based lipid analogue bearing a bulky <i>tert</i>-butyl group at the 4-position of the terminal benzene ring exhibited
potent GPR34 agonistic activity, validating the present hydrophobic
binding pocket model
Separation and quantification of 2-acyl-1-lysophospholipids and 1-acyl-2-lysophospholipids in biological samples by LC-MS/MS
Probing the Hydrophobic Binding Pocket of G‑Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS<sub>1</sub> by Docking-Aided Structure–Activity Analysis
The
ligands of certain G-protein-coupled receptors (GPCRs) have
been identified as endogenous lipids, such as lysophosphatidylserine
(LysoPS). Here, we analyzed the molecular basis of the structure–activity
relationship of ligands of GPR34, one of the LysoPS receptor subtypes,
focusing on recognition of the long-chain fatty acid moiety by the
hydrophobic pocket. By introducing benzene ring(s) into the fatty
acid moiety of 2-<i>deoxy</i>-LysoPS, we explored the binding
site’s preference for the hydrophobic shape. A tribenzene-containing
fatty acid surrogate with modifications of the terminal aromatic moiety
showed potent agonistic activity toward GPR34. Computational docking
of these derivatives with a homology modeling/molecular dynamics-based
virtual binding site of GPR34 indicated that a kink in the benzene-based
lipid surrogates matches the L-shaped hydrophobic pocket of GPR34.
A tetrabenzene-based lipid analogue bearing a bulky <i>tert</i>-butyl group at the 4-position of the terminal benzene ring exhibited
potent GPR34 agonistic activity, validating the present hydrophobic
binding pocket model
Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity
Lysophosphatidylserine (LysoPS) is
an endogenous lipid mediator
that specifically activates membrane proteins of the P2Y and its related
families of G protein-coupled receptors (GPCR), GPR34 (LPS<sub>1</sub>), P2Y10 (LPS<sub>2</sub>), and GPR174 (LPS<sub>3</sub>). Here, in
order to increase potency and receptor selectivity, we designed and
synthesized LysoPS analogues containing the conformational constraints
of the glycerol moiety. These reduced structural flexibility by fixation
of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran
skeleton, and related structures identified compounds which exhibited
high potency and selectivity for activation of GPR34 or P2Y10. Morphing
of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran
skeleton into a planar benzene ring enhanced the P2Y10 activation
potentcy rather than the GPR34 activation
Structure–Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G‑Protein-Coupled Receptors GPR34, P2Y10, and GPR174
Lysophosphatidylserine
(LysoPS) is an endogenous lipid mediator
generated by hydrolysis of membrane phospholipid phosphatidylserine.
Recent ligand screening of orphan G-protein-coupled receptors (GPCRs)
identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS<sub>2</sub>) and GPR174 (LPS<sub>3</sub>), which, together with previously
reported GPR34 (LPS<sub>1</sub>), comprise a LysoPS receptor family.
Herein, we examined the structure–activity relationships of
a series of synthetic LysoPS analogues toward these recently deorphanized
LysoPS receptors, based on the idea that LysoPS can be regarded as
consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting
from the endogenous ligand (1-oleoyl-LysoPS, <b>1</b>), we optimized
the structure of each module and the ester linkage. Accordingly, we
identified some structural requirements of each module for potency
and for receptor subtype selectivity. Further assembly of individually
structure-optimized modules yielded a series of potent and LysoPS
receptor subtype-selective agonists, particularly for P2Y10 and GPR174