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Abstract

Zhankuic acid A (ZAA) is the major pharmacologically active compound of Taiwanofungus camphoratus. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two antibodies 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 antibody 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 indicate that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, is a potential therapeutic agent for Gram-negative bacterial infections.

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First Claim