title: Zhankuic acid A isolated from Taiwanofungus camphoratus is a novel selective TLR4/MD-2 antagonist with anti-inflammatory properties.
abstract: TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two Abs against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced Ab recognition to native MD-2, similar to the effect of LPS binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections.
authors.affiliation: Institute of Life Sciences, National Cheng Kung University, Tainan 70101, Taiwan;
authors.forename: Yu-Fon
authors.initials: YF
authors.lastname: Chen
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Shiau
authors.forename: Sheng-Hung
authors.initials: SH
authors.lastname: Wang
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Sue-Joan
authors.initials: SJ
authors.lastname: Chang
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Wu
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001487:Basidiomycota / Q000737:chemistry*; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology / Q000517:prevention & control; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D012480:Salmonella Infections / Q000150:complications; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4; C098367:zhankuic acid A; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D004875:Ergosterol