title: A novel benzenediamine derivate rescued mice from experimental sepsis by attenuating proinflammatory mediators via IRAK4.
abstract: We designed and synthesized a novel benzenediamine derivate, FC-99, that was tested for its ability to protect mice from experimental sepsis. Moreover, we sought to determine whether FC-99 could control a bacterial infection and to clarify the mechanism by which FC-99 inhibited LPS-activated macrophages. The effects of FC-99 on inflammation were evaluated in two experimental sepsis models and in cultured macrophages. Microarrays and docking and molecular dynamics simulations were used to determine the target of FC-99. Surface plasmon resonance and molecular detection were performed to confirm the direct interaction of FC-99 with its target. FC-99 protected mice from experimental sepsis. The mice that received FC-99 exhibited a diminished inflammatory response, had a lower local bacterial burden, and experienced a significantly improved survival rate. Genome-wide transcriptional profiling of FC-99-treated macrophages identified IRAK4 as a drug-regulated gene involved in LPS/TLR4 signaling. A computer search and calculations indicated that IRAK4 directly interacted with FC-99. Surface plasmon resonance, IRAK4-regulated signaling pathway analysis, and gene expression profiling of proinflammatory mediators confirmed the direct interaction between FC-99 and IRAK4. FC-99 is a potential therapeutic molecule for sepsis that alleviated experimental sepsis by directly inhibiting IRAK4 activation, which represents a novel target for sepsis therapy.
authors.affiliation: 1 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School.
authors.forename: Huan
authors.initials: H
authors.lastname: Dou
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Song
authors.forename: Xianqin
authors.initials: X
authors.lastname: Liu
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Dai
authors.initials: D
authors.lastname: Chen
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D015398:Signal Transduction / Q000187:drug effects*; D020349:Surface Plasmon Resonance; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D003959:Diamines; D018836:Inflammation Mediators; C000598432:N1-((4-methoxy)methyl)-4-methyl-1,2-benzenediamine; D010655:Phenylenediamines; D047428:Protein Kinase Inhibitors; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse
keywords: FC-99; IRAK4; inflammation; macrophage; sepsis