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Discovery of Novel Sesquiterpene Lactone Derivatives as Potent PKM2 Activators for the Treatment of Ulcerative Colitis. 2023

Ping Wang, and Hongqiong Yang, and Weijiang Lin, and Jingxian Zhou, and Yi Liu, and Lingyu Ma, and Mengting Li, and Yang Hu, and Chengli Yu, and Yinan Zhang, and Qi Lv, and Jian Liu, and Lihong Hu
Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.

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.

UI MeSH Term Description Entries
D003092 Colitis Inflammation of the COLON section of the large intestine (INTESTINE, LARGE), usually with symptoms such as DIARRHEA (often with blood and mucus), ABDOMINAL PAIN, and FEVER. Colitides
D003093 Colitis, Ulcerative Inflammation of the COLON that is predominantly confined to the MUCOSA. Its major symptoms include DIARRHEA, rectal BLEEDING, the passage of MUCUS, and ABDOMINAL PAIN. Colitis Gravis,Idiopathic Proctocolitis,Inflammatory Bowel Disease, Ulcerative Colitis Type,Ulcerative Colitis
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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