公开(公告)号：US5837852A

公开(公告)日：1998-11-17

申请号：US136214

申请日：1993-10-14

申请人： Thomas D. Y. Chung ,  Christopher W. Cianci ,  Moira Hagen ,  Mark Krystal ,  Richard J. Colonno

发明人： Thomas D. Y. Chung ,  Christopher W. Cianci ,  Moira Hagen ,  Mark Krystal ,  Richard J. Colonno

IPC分类号： A61K38/00 ,  C07H21/00 ,  C12N15/113 ,  C12N5/00 ,  A61K48/00 ,  C12N15/00 ,  C07N14/00

CPC分类号： C12N15/1131 ,  C07H21/00 ,  A61K38/00 ,  C12N2310/13 ,  C12N2310/317

摘要： Novel capped oligonucleotides useful in treatment of influenza infection. A synthetically derived 67-nucleotide RNA substrate, containing a �.sup.32 P! labeled cap-1 structure was used to analyze parameters of influenza virus endonuclease activity. This substrate was specifically cleaved by the influenza virus polymerase to yield a single capped 11-nucleotide fragment capable of directly priming transcription. An analysis of systematic truncations of this RNA substrate in cleavage, elongation, and binding reactions demonstrated that the minimum chain length required for cleavage was one nucleotide past the cleavage site. In contrast, the minimum chain length required for priming activity was found to be 9 nucleotides, while a chain length of at least 4 nucleotides was required for efficient binding. Based on these chain length requirements, the present inventors show that a pool of capped oligonucleotides--too short to prime transcription but long enough to bind with high affinity to the viral polymerase--are potent inhibitors of cap-dependent in vitro transcription.

摘要翻译： 用于治疗流感感染的新型封端寡核苷酸。 使用含有[32P]标记的cap-1结构的合成衍生的67-核苷酸RNA底物来分析流感病毒核酸内切酶活性的参数。 该底物被流感病毒聚合酶特异地切割，得到能够直接引发转录的单一封端的11-核苷酸片段。 在裂解，延伸和结合反应中对该RNA底物的系统截短的分析表明，切割所需的最短链长度是经过切割位点的一个核苷酸。 相比之下，发现引发活性所需的最短链长度为9个核苷酸，而需要至少4个核苷酸的链长才能有效结合。 基于这些链长度要求，本发明人表明，封闭的寡核苷酸库 - 太短而不能提供转录但足够长以高度结合到病毒聚合酶 - 是帽依赖性体外转录的有效抑制剂。

公开(公告)号：US20140011700A1

公开(公告)日：2014-01-09

申请号：US14003003

申请日：2012-03-23

申请人： Eric T. Baldwin ,  Patricia Ann McDonnell ,  Suzanne Edavettal ,  Hal Lewis ,  Bradley C. Pearce ,  David R. Langley ,  Christopher W. Cianci ,  Linda Discotto ,  Samuel Gerritz ,  Shuhao Shi ,  Shirong Zhu

发明人： Eric T. Baldwin ,  Patricia Ann McDonnell ,  Suzanne Edavettal ,  Hal Lewis ,  Bradley C. Pearce ,  David R. Langley ,  Christopher W. Cianci ,  Linda Discotto ,  Samuel Gerritz ,  Shuhao Shi ,  Shirong Zhu

IPC分类号： C07K14/005 ,  G01N33/68

CPC分类号： C07K14/005 ,  A61K38/00 ,  C12N2760/16122 ,  G01N33/6875

摘要： The binding mode of the antiviral compounds have been characterized through a variety of biophysical and structural studies, elaborating on the proposed aggregation mechanism of action. We demonstrate the direct binding of these antiviral compounds to NP using thermal shift enhancement assay (TSE) and NMR. In addition, we have completed a detailed analysis of the oligomerization mechanism of action using dynamic light scattering, analytical ultracentrifugation, and surface plasmon resonance (SPR). Structure determination using x-ray crystallography confirmed the proposed compound-induced oligomerization mechanism of action. The co-crystal structure revealed that two compounds bound in an anti-parallel fashion bridging two NP monomers, inducing a novel non-native NP oligomer. Taken together, our data suggest a complex binding mode in which the compounds bind NP specifically in stoichiometric fashion inducing the formation of an NP oligomer without obstructing the RNA binding pocket or interfering with the native NP homo-oligomerization.

摘要翻译： 抗病毒化合物的结合模式已经通过各种生物物理和结构研究来表征，详细阐述了提出的聚集作用机制。 我们使用热移位增强测定（TSE）和NMR证明了这些抗病毒化合物与NP的直接结合。 另外，我们已经完成了使用动态光散射，分析超速离心和表面等离子体共振（SPR）的作用的低聚机理的详细分析。 使用x射线晶体学的结构测定证实了所提出的化合物诱导的低聚作用机制。 共晶结构显示两种化合物以反平行方式结合，桥接两个NP单体，诱导新型非天然NP寡聚体。 综合起来，我们的数据表明了复合结合模式，其中化合物以化学计量的方式特异性结合NP，诱导NP寡聚体的形成，而不会阻碍RNA结合口袋或干扰天然的NP均聚低聚。

公开(公告)号：US20120245176A1

公开(公告)日：2012-09-27

申请号：US13242676

申请日：2011-09-23

申请人： Christopher W. Cianci ,  Samuel Gerritz ,  Sean Kim ,  David R. Langley ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

发明人： Christopher W. Cianci ,  Samuel Gerritz ,  Sean Kim ,  David R. Langley ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

IPC分类号： A61K31/496 ,  C07D413/14 ,  A61K31/506 ,  A61P31/16 ,  C07D403/06 ,  C07D401/14 ,  C07D417/06 ,  A61P31/12 ,  C07D413/06 ,  A61K31/498

CPC分类号： C07D413/06 ,  C07D403/06 ,  C07D413/14

摘要： A compound of Formula I is set forth, including pharmaceutically acceptable salts thereof: wherein Het is a 5 or 6-membered heterocycle with —N, —O, or —S adjacent to the —Ar substituent or adjacent to the point of attachment for the —Ar substituent; Ar is aryl or heteroaryl; R is —CH3, —CH2F, —CHF2 or —CH═CH2; V is —H, —CH3 or ═O; W is —NO2, —Cl, —Br, —CH2OH, or —CN; X is —Cl, —Br, —F, —CH3, —OCH3, or —CN; Y is —CH or —N; and Z is —CH or —N. This compound is useful in compositions for the prevention and treatment of influenza virus.

摘要翻译： 提出了式I的化合物，包括其药学上可接受的盐：其中Het是与-Ar取代基相邻的具有-N，-O或-S的5或6元杂环，或邻近-Ar取代基的连接点 -Ar取代基; Ar是芳基或杂芳基; R是-CH 3，-CH 2 F，-CHF 2或-CH = CH 2; V是-H，-CH 3或= O; W是-NO 2，-Cl，-Br，-CH 2 OH或-CN; X是-Cl，-Br，-F，-CH 3，-OCH 3或-CN; Y是-CH或-N; 并且Z是-CH或-N。 该化合物可用于预防和治疗流感病毒的组合物。

公开(公告)号：US08362004B2

公开(公告)日：2013-01-29

申请号：US13225851

申请日：2011-09-06

申请人： Christopher W. Cianci ,  Samuel Gerritz ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

发明人： Christopher W. Cianci ,  Samuel Gerritz ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

IPC分类号： A61K31/397 ,  A61K31/496 ,  C07D403/04 ,  C07D403/14 ,  C07D413/04 ,  C07D413/14

CPC分类号： C07D261/18 ,  C07D207/327 ,  C07D231/14 ,  C07D233/90 ,  C07D249/06 ,  C07D403/12 ,  C07D413/12 ,  C07D417/12

摘要： A compound of Formula I is set forth, including pharmaceutically acceptable salts thereof: wherein Het is a 5 or 6-membered heterocycle with —N, —O, or —S adjacent to the —Ar substituent or adjacent to the point of attachment for the —Ar substituent; Ar is aryl or heteroaryl; R is —CH3, —CH2F, or —CH═CH2; W is —NO2, —Cl, —Br, —CHO, —CH═CH2, or —CN; X is —Cl, —CH3, or —CN; Y is —CH or —N; and Z is C1-C6 alkyl, C3-C6 cycloalkyl, substituted aryl, substituted heteroaryl, OR1, or NHR1, wherein R1 is selected from the group of H, aryl, heteroaryl, C1-C6 alkyl and C3-C6 cycloalkyl. This compound is useful in compositions for the prevention and treatment of influenza virus.

摘要翻译： 提出了式I的化合物，包括其药学上可接受的盐：其中Het是与-Ar取代基相邻的具有-N，-O或-S的5或6元杂环，或邻近-Ar取代基的连接点 -Ar取代基; Ar是芳基或杂芳基; R是-CH 3，-CH 2 F或-CH = CH 2; W是-NO 2，-Cl，-Br，-CHO，-CH = CH 2或-CN; X是-Cl，-CH 3或-CN; Y是-CH或-N; 并且Z是C 1 -C 6烷基，C 3 -C 6环烷基，取代的芳基，取代的杂芳基，OR 1或NHR 1，其中R 1选自H，芳基，杂芳基，C 1 -C 6烷基和C 3 -C 6环烷基。 该化合物可用于预防和治疗流感病毒的组合物。

公开(公告)号：US20120238539A1

公开(公告)日：2012-09-20

申请号：US13225851

申请日：2011-09-06

申请人： Christopher W. Cianci ,  Samuel Gerritz ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

发明人： Christopher W. Cianci ,  Samuel Gerritz ,  Guo Li ,  Bradley C. Pearce ,  Annapurna Pendri ,  Shuhao Shi ,  Weixu Zhai ,  Shirong Zhu

IPC分类号： A61K31/496 ,  C07D413/14 ,  A61P31/16 ,  A61K31/5355 ,  C07D403/14 ,  A61P31/12 ,  C07D413/06 ,  C07D417/14

CPC分类号： C07D261/18 ,  C07D207/327 ,  C07D231/14 ,  C07D233/90 ,  C07D249/06 ,  C07D403/12 ,  C07D413/12 ,  C07D417/12

摘要： A compound of Formula I is set forth, including pharmaceutically acceptable salts thereof: wherein Het is a 5 or 6-membered heterocycle with —N, —O, or —S adjacent to the —Ar substituent or adjacent to the point of attachment for the —Ar substituent; Ar is aryl or heteroaryl; R is —CH3, —CH2F, or —CH═CH2; W is —NO2, —Cl, —Br, —CHO, —CH═CH2, or —CN; X is —Cl, —CH3, or —CN; Y is —CH or —N; and Z is C1-C6 alkyl, C3-C6 cycloalkyl, substituted aryl, substituted heteroaryl, OR1, or NHR1, wherein R1 is selected from the group of H, aryl, heteroaryl, C1-C6 alkyl and C3-C6 cycloalkyl. This compound is useful in compositions for the prevention and treatment of influenza virus.

摘要翻译： 提出了式I的化合物，包括其药学上可接受的盐：其中Het是与-Ar取代基相邻的具有-N，-O或-S的5或6元杂环，或邻近-Ar取代基的连接点 -Ar取代基; Ar是芳基或杂芳基; R是-CH 3，-CH 2 F或-CH = CH 2; W是-NO 2，-Cl，-Br，-CHO，-CH = CH 2或-CN; X是-Cl，-CH 3或-CN; Y是-CH或-N; 并且Z是C 1 -C 6烷基，C 3 -C 6环烷基，取代的芳基，取代的杂芳基，OR 1或NHR 1，其中R 1选自H，芳基，杂芳基，C 1 -C 6烷基和C 3 -C 6环烷基。 该化合物可用于预防和治疗流感病毒的组合物。