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Myeloid differentiation 2 (<jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>\u20102) is required for recognizing lipopolysaccharide (<jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>) by toll\u2010like receptor 4 (<jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4), and represents an attractive therapeutic target for <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>2 inhibitor, which could inhibit <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010induced inflammation both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. We identify that L2H21 as a direct inhibitor of <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>\u20102 by binding to Arg<jats:sup>90<\/jats:sup> and Tyr<jats:sup>102<\/jats:sup> residues in <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>\u20102 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation. L2H21 dose dependently inhibited <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010induced inflammatory cytokine expression in primary macrophages. In mice with <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> intratracheal instillation, L2H21 significantly decreased <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010induced pulmonary oedema, pathological changes in lung tissue, protein concentration increase in bronchoalveolar lavage fluid, inflammatory cells infiltration and inflammatory gene expression, accompanied with the decrease in pulmonary <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4\/<jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>\u20102 complex. Meanwhile, administration with L2H21 protects mice from <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010induced mortality at a degree of 100%. Taken together, this study identifies a new <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>2 inhibitor L2H21 as a promising candidate for the treatment of acute lung injury (<jats:styled-content style=\"fixed-case\">ALI<\/jats:styled-content>) and sepsis, and validates that inhibition of <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>\u20102 is a potential therapeutic strategy for <jats:styled-content style=\"fixed-case\">ALI<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/jcmm.13017","type":"journal-article","created":{"date-parts":[[2016,11,18]],"date-time":"2016-11-18T09:42:45Z","timestamp":1479462165000},"page":"746-757","source":"Crossref","is-referenced-by-count":24,"title":["Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects <scp>LPS<\/scp>\u2010induced acute lung injury"],"prefix":"10.1111","volume":"21","author":[{"given":"Yali","family":"Zhang","sequence":"first","affiliation":[{"name":"Chemical Biology 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