Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
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DOI：
10.1021/cb400400j
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发表时间：
2013-11-15
影响因子：
4
通讯作者：
Arnold, Eddy
中科院分区：
文献类型：
--
作者：
Bauman, Joseph D.;Patel, Disha;Baker, Steven F.;Vijayan, R. S. K.;Xiang, Amy;Parhi, Ajit K.;Martinez-Sobrido, Luis;LaVoie, Edmond J.;Das, Kalyan;Arnold, Eddy
季节性和大流行性流感病毒仍然是全球主要的健康问题。对当前药物的新出现的耐药性和疫苗的可变效力强调了开发新的流感药物的必要性，这些药物将对野生型和耐药性流感毒株广泛有效。在这里，我们报告了一类针对病毒聚合酶的夺帽核酸内切酶活性的抑制剂的发现和发展。对2009年H1N1流感大流行聚合酶酸性蛋白N-末端核酸内切酶结构域（PAN）的高分辨率晶体形式进行工程化，并用于片段筛选，从而鉴定与PAN活性位点裂缝结合的新化学支架。在筛选过程中，在PAN的活性位点裂缝中检测到与核酸内切酶活性潜在相关的第三金属离子的结合。使用基于结构的优化，我们开发了一种高效的羟基吡啶酮系列化合物，从片段命中，定义了一种新的模式螯合到活性位点的金属离子。在基于荧光的酶试验中显示出有希望的酶抑制作用（IC 50值为11 nM）的系列化合物在MDCK细胞中对PR 8 H1N1甲型流感病毒具有11 μM的抗病毒活性（EC 50）。
Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity, was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.
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影响因子：
7.3
作者：
Bauman, Joseph D.;Patel, Disha;Dharia, Chhaya;Fromer, Marc W.;Ahmed, Sameer;Frenkel, Yulia;Vijayan, R. S. K.;Eck, J. Thomas;Ho, William C.;Das, Kalyan;Shatkin, Aaron J.;Arnold, Eddy
通讯作者：
Arnold, Eddy
影响因子：
4.9
作者：
Hastings, JC;Selnick, H;Tomassini, JE
通讯作者：
Tomassini, JE
影响因子：
2.9
作者：
Doan, L;Handa, B;Klumpp, K
通讯作者：
Klumpp, K
影响因子：
7.3
作者：
Das, Kalyan
通讯作者：
Das, Kalyan
DOI：
10.3390/v2081510
发表时间：
2010-08
期刊：
Viruses
影响因子：
--
作者：
Govorkova EA;Webster RG
通讯作者：
Webster RG