Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.
Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.
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DOI：
10.1021/jm301694x
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发表时间：
2013-06-13
影响因子：
7.3
通讯作者：
Cottamt, Howard B.
中科院分区：
文献类型：
--
作者：
Chan, Michael;Hayashi, Tomoko;Mathewson, Richard D.;Nour, Afshin;Hayashi, Yuki;Yao, Shiyin;Tawatao, Rommel I.;Crain, Brian;Tsigelny, Igor F.;Kouznetsoya, Valentina L.;Messer, Karen;Pu, Minya;Corr, Maripat;Carson, Dennis A.;Cottamt, Howard B.
基于细胞的高通量筛选鉴定先天免疫系统的小分子量刺激物显示取代嘧啶[5,4-b]吲哚是有效的NFκB激活剂。最有效的打击化合物选择性地刺激toll样受体4 （TLR4）在人和小鼠细胞。对嘧啶[5,4-b]吲哚支架在羧基酰胺、N-3和N-5位点的合成修饰表明，TLR4依赖性NFκB和I型干扰素相关细胞因子、IL-6和干扰素γ诱导蛋白10 （IP-10）的产生存在差异。具体来说，含有苯基和取代苯基羧酰胺的化合物亚群诱导较低的IL-6释放，同时保持较高的IP-10产生，偏向I型干扰素途径。在N-5上用短烷基取代降低了前导被击中化合物的细胞毒性。计算研究支持，活性化合物似乎主要与TLR4/MD-2复合物中的MD-2结合。这些小分子以最小的毒性刺激先天免疫细胞，可能被用作佐剂或免疫调节剂。
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
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影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
4.8
作者：
Meng, Jianmin;Drolet, Joshua R.;Golenbock, Douglas T.
通讯作者：
Golenbock, Douglas T.
DOI：
10.1073/pnas.0631696100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Lee, J;Chuang, TH;Cottam, HB
通讯作者：
Cottam, HB
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh