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.