MD2-IN-1

Description: MD2-IN-1, a chalcone derivative, is a novel potent and specific inhibitor of Myeloid differentiation protein 2 (MD2) with a KD of 189 ?uM for the recombinant human MD2 (rhMD2). Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co-receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases.MD2-IN-1 contains the moiety of (E)-4-phenylbut-3-en-2-one, which is considered to be the core structure of current MD2 inhibitors. The anti-inflammatory activities of MD2-IN-1 was evaluated in MPMs. MD2-IN-1 binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg(90) and Tyr(102) residues. MD2-IN-1 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-kappaB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with MD2-IN-1 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives is a potential candidate for treating acute inflammatory diseases.

References: Sci Rep. 2016 Apr 27; 6:25130.