Discovery of Novel Sesquiterpene Lactone Derivatives as Potent PKM2 Activators for the Treatment of Ulcerative Colitis

The pyruvate kinase M2 (PKM2) can significantly affect
the differentiation
of Th17 and Treg cells; thus, it is considered a promising target
for UC therapy. Herein, five series of costunolide (Cos) derivatives are designed, synthesized, and biologically
evaluated. Among them, D5 exhibits excellent immunomodulatory
activity against T-cell proliferation and potent PKM2 activating activity.
Meanwhile, it has been confirmed that D5 can also covalently
interact with Cys424 of PKM2. The molecular docking and molecular
dynamic (MD) studies indicate that difluorocyclopropyl derivative
of D5 improves the protein–ligand interaction
by interacting with Arg399 electrostatically. Furthermore, D5 significantly dampens the differentiation of Th17 but not Treg cells
to recover the Th17/Treg balance, which is attributed to the suppression
of PKM2-mediated glycolysis. Oral administration of D5 ameliorates the symptoms of dextran sulfate sodium (DSS)- and 2,4,6-trinitro-benzenesulfonic
acid (TNBS)-induced colitis in mouse model. Collectively, D5 has the potential to be developed as a novel anti-UC candidate.