Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors.
Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors.
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DOI：
10.1371/journal.pone.0065779
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hackam DJ
中科院分区：
文献类型：
--
作者：
Neal MD;Jia H;Eyer B;Good M;Guerriero CJ;Sodhi CP;Afrazi A;Prindle T Jr;Ma C;Branca M;Ozolek J;Brodsky JL;Wipf P;Hackam DJ
许多炎性疾病可能与通过脂多糖（LPS）受体、toll样受体4（TLR 4）的病理性升高的信号传导有关。因此，人们对发现TLR 4抑制剂作为潜在的抗炎剂产生了极大的兴趣。最近，TLR 4与抑制剂E5564结合的结构被解决，提高了设计靶向E5564结合结构域的新型TLR 4抑制剂的可能性。我们利用相似性搜索算法结合小分子文库的有限筛选方法来鉴定与E5564位点结合并抑制TLR 4的化合物。我们的先导化合物C34是一种2-乙酰氨基吡喃糖苷（MW 389），分子式为C17 H27 NO 9，可在体外抑制肠细胞和巨噬细胞中的TLR 4，并减少内毒素血症和坏死性小肠结肠炎小鼠模型中的全身炎症。C34与TLR 4共受体MD-2的疏水内部口袋的分子对接证明了紧密配合，将吡喃环深深嵌入口袋内。引人注目的是，C34在从患有坏死性小肠结肠炎的婴儿切除的人回肠中离体抑制LPS信号传导。这些发现将C34和β-异头环己基类似物C35鉴定为小分子TLR 4抑制剂的新先导物，所述小分子TLR 4抑制剂对TLR 4介导的炎性疾病具有潜在治疗益处。
Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases.
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DOI：
10.4049/jimmunol.1103114
发表时间：
2012-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Afrazi A;Sodhi CP;Good M;Jia H;Siggers R;Yazji I;Ma C;Neal MD;Prindle T;Grant ZS;Branca MF;Ozolek J;Chang EB;Hackam DJ
通讯作者：
Hackam DJ
影响因子：
3.6
作者：
Afrazi A;Sodhi CP;Richardson W;Neal M;Good M;Siggers R;Hackam DJ
通讯作者：
Hackam DJ
DOI：
10.1007/978-0-387-74087-4_18
发表时间：
2008-01-01
期刊：
BIOACTIVE COMPONENTS OF MILK
影响因子：
--
作者：
Kunz, C.;Rudloff, S.
通讯作者：
Rudloff, S.
影响因子：
6.7
作者：
Awla, Darbaz;Abdulla, Aree;Thorlacius, Henrik
通讯作者：
Thorlacius, Henrik
影响因子：
4.4
作者：
Leaphart, Cynthia L.;Cavallo, Jaime;Hackam, David J.
通讯作者：
Hackam, David J.