1 research outputs found
Identification of a New Type of Covalent PPARĪ³ Agonist using a Ligand-Linking Strategy
Peroxisome proliferator-activated
receptor Ī³ (PPARĪ³)
is a ligand-activated transcription factor that plays an important
role in adipogenesis and glucose metabolism. The ligand-binding pocket
(LBP) of PPARĪ³ has a large Y-shaped cavity with multiple subpockets
where multiple ligands can simultaneously bind and cooperatively activate
PPARĪ³. Focusing on this unique property of the PPARĪ³ LBP,
we describe a novel two-step cell-based strategy to develop PPARĪ³
ligands. First, a combination of ligands that cooperatively activates
PPARĪ³ was identified using a luciferase reporter assay. Second,
hybrid ligands were designed and synthesized. For proof of concept,
we focused on covalent agonists, which activate PPARĪ³ through
a unique activation mechanism regulated by a covalent linkage with
the Cys285 residue in the PPARĪ³ LBP. Despite their biological
significance and pharmacological potential, few covalent PPARĪ³
agonists are known except for endogenous fatty acid metabolites. With
our strategy, we determined that plant-derived cinnamic acid derivatives
cooperatively activated PPARĪ³ by combining with GW9662, an irreversible
antagonist. GW9662 covalently reacts with the Cys285 residue. A docking
study predicted that a cinnamic acid derivative can bind to the open
cavity in GW9662-bound PPARĪ³ LBP. On the basis of the putative
binding mode, structures of both ligands were linked successfully
to create a potent PPARĪ³ agonist, which enhanced the transactivation
potential of PPARĪ³ at submicromolar levels through covalent
modification of Cys285. Our approach could lead to the discovery of
novel high-potency PPARĪ³ agonists