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    IDENTIFICATION OF MODULATORS OF SERINE PROTEASE INHIBITOR KAZAL AND THEIR USE AS ANTI-CANCER AND ANTI-VIRAL AGENTS
    21.
    发明申请
    IDENTIFICATION OF MODULATORS OF SERINE PROTEASE INHIBITOR KAZAL AND THEIR USE AS ANTI-CANCER AND ANTI-VIRAL AGENTS 审中-公开
    丝氨酸蛋白酶抑制剂KAZAL调节剂的鉴定及其作为抗癌剂和抗病毒剂的用途

    公开(公告)号：US20130280255A1

    公开(公告)日：2013-10-24

    申请号：US13937153

    申请日：2013-07-08

    申请人： Xuanyong Lu ,  Timothy M. Block

    发明人： Xuanyong Lu ,  Timothy M. Block

    IPC分类号： C12Q1/37

    CPC分类号： C12Q1/37 ,  G01N2333/96433 ,  G01N2500/02

    摘要： This disclosure describes a relevant etiology of cancer and a novel anti-cancer therapeutic strategy, based on the discovery that a protein named serine protease inhibitor (SPIK/SPINK/PSTI) was up-regulated by hepatitis B and C virus infections consequently suppressing the cell apoptosis. Accordingly, the present disclosure provides, inter alia, an inhibitor of SPIK and/or a technology of suppression of over-expression of SPIK in cells. The inhibitors include: 1) chemical compounds, which can inhibit SPIK transcripts, protein activity, and gene expression, 2) SPIK siRNA (RNAi gene silence or dsRNA of SPIK, 3) DNA anti-sense and anti-SPIK antibody. Further, this disclosure provides methods of using the inhibitor as an anti-cancer agent to re-instate cancer cell apoptosis (e.g., serine protease dependent cell apoptosis).

    摘要翻译： 本公开描述了癌症的相关病因和新型抗癌治疗策略，基于以下发现：称为丝氨酸蛋白酶抑制剂（SPIK / SPINK / PSTI）的蛋白质被乙型和丙型肝炎病毒感染上调，从而抑制细胞 凋亡。 因此，本公开尤其提供SPIK抑制剂和/或抑制细胞中SPIK过度表达的技术。 抑制剂包括：1）可抑制SPIK转录物，蛋白质活性和基因表达的化合物，2）SPIK siRNA（SPIK的RNAi基因沉默或dsRNA，3）DNA反义和抗SPIK抗体。 此外，本公开提供使用抑制剂作为抗癌剂来重新制备癌细胞凋亡（例如，丝氨酸蛋白酶依赖性细胞凋亡）的方法。

    Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity and Reducted Toxicity
    22.
    发明申请
    Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity and Reducted Toxicity 有权
    新型伊米诺糖衍生物证明有效的抗病毒活性和减少的毒性

    公开(公告)号：US20110189771A1

    公开(公告)日：2011-08-04

    申请号：US13061734

    申请日：2009-09-02

    申请人： Timothy M. Block ,  Jinhong Chang ,  Xiaodong Xu

    发明人： Timothy M. Block ,  Jinhong Chang ,  Xiaodong Xu

    IPC分类号： C12N5/02 ,  C07D211/40

    CPC分类号： A61K31/47 ,  A61K31/7056 ,  C07D211/46 ,  Y02A50/393 ,  A61K2300/00

    摘要： Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

    摘要翻译： 诸如脱氧野尻霉素（DNJ）的亚氨基糖是选择性抑制细胞α-葡萄糖苷酶I和II（在糖蛋白中处理N-连接聚糖的酶）并且对许多包膜病毒展现广谱抗病毒活性的葡萄糖类似物。 以前我们已经报道了具有抗病毒活性和降低的细胞毒性的新型DNJ衍生物OSL-95II。 为了开发具有更强的抗病毒活性和改善的毒性特征的亚氨基糖，OSL-95II通过使氮连接的烷基化侧链多样化而被修饰。 首先在牛病毒性腹泻病毒（BVDV）感染的MDBK细胞中测试抗病毒活性，产生几种具有新结构和优良抗病毒活性和毒性特征的亚氨基糖衍生物。 此外，这些新化合物被证明对BHK细胞中登革热病毒（DV）和西尼罗病毒（WNV）感染具有活性，其中具有亚微摩尔EC 50值和SI大于900的有效抗DV活性。这些化合物代表新一代 的亚氨基糖及其类似物，可用于临床治疗DV和其他黄病毒成分的感染。

    METHOD OF TUMOR SCREENING
    23.
    发明申请
    METHOD OF TUMOR SCREENING 审中-公开
    肿瘤筛查方法

    公开(公告)号：US20100285469A1

    公开(公告)日：2010-11-11

    申请号：US12680654

    申请日：2008-10-10

    申请人： Ying-Hsiu Su ,  Zhili Wang ,  Timothy M. Block ,  Janet Song

    发明人： Ying-Hsiu Su ,  Zhili Wang ,  Timothy M. Block ,  Janet Song

    IPC分类号： C12Q1/68

    CPC分类号： C12Q1/6886 ,  C12N15/1013 ,  C12Q1/6806 ,  C12Q2600/112 ,  C12Q2563/143 ,  C12Q2527/125 ,  C12Q2525/204

    摘要： A method for tumor screening using urine of a mammal, the method includes obtaining a total urine nucleic acid (e.g., DNA) from a urine sample of a mammal, extracting a high molecular weight urine nucleic acid (above 1000 bp) by contacting the total urine nucleic acid with an adsorbent in the presence of a buffer which promotes binding of the high molecular weight urine nucleic acid to the adsorbent, replacing the buffer which promotes binding of the high molecular weight urine nucleic acid with a buffer which promotes binding of the low molecular weight urine nucleic acid to the adsorbent, extracting the low molecular weight urine nucleic acid by contacting with the adsorbent, eluting the low molecular weight urine nucleic acid, and assaying the low molecular weight urine nucleic acid for a presence or absence of a gene sequence specific to a certain type of tumor.

    摘要翻译： 一种使用哺乳动物的尿液进行肿瘤筛选的方法，所述方法包括从哺乳动物的尿液样品中获得总的尿核酸（例如DNA），通过使总共接触总共提取高分子量的尿核酸（1000bp以上） 尿素核酸与缓冲液的存在有助于促进高分子量尿核酸与吸附剂的结合，代替促进高分子量尿核酸与促进低分子量尿核酸结合的缓冲液 分子量的尿核酸加入到吸附剂中，通过与吸附剂接触，洗脱低分子量尿核酸，并测定低分子量尿核酸是否存在基因序列来提取低分子量尿核酸 特定于某种类型的肿瘤。

    Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity
    25.
    发明授权
    Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity 有权
    亚氨基糖衍生物表现出强大的抗病毒活性和降低的毒性

    公开(公告)号：US09040488B2

    公开(公告)日：2015-05-26

    申请号：US13061734

    申请日：2009-09-02

    申请人： Timothy M. Block ,  Jinhong Chang ,  Xiaodong Xu

    发明人： Timothy M. Block ,  Jinhong Chang ,  Xiaodong Xu

    IPC分类号： C07D211/46 ,  A61K31/445 ,  A61K31/47 ,  A61K31/7056

    CPC分类号： A61K31/47 ,  A61K31/7056 ,  C07D211/46 ,  Y02A50/393 ,  A61K2300/00

    摘要： Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

    摘要翻译： 诸如脱氧野尻霉素（DNJ）的亚氨基糖是选择性抑制细胞α-葡萄糖苷酶I和II（在糖蛋白中加工N-连接聚糖的酶）并且对许多包膜病毒展现广谱抗病毒活性的葡萄糖类似物。 以前我们已经报道了具有抗病毒活性和降低的细胞毒性的新型DNJ衍生物OSL-95II。 为了开发具有更强的抗病毒活性和改善的毒性特征的亚氨基糖，OSL-95II通过使氮连接的烷基化侧链多样化而被修饰。 首先在牛病毒性腹泻病毒（BVDV）感染的MDBK细胞中测试抗病毒活性，产生几种具有新结构和优良抗病毒活性和毒性特征的亚氨基糖衍生物。 此外，这些新化合物被证明对BHK细胞中登革热病毒（DV）和西尼罗病毒（WNV）感染具有活性，其中具有亚微摩尔EC 50值和SI大于900的有效抗DV活性。这些化合物代表新一代 的亚氨基糖及其类似物，可用于临床治疗DV和其他黄病毒成分的感染。

    SERINE PROTEASE INHIBITOR KAZAL ANTIBODIES
    26.
    发明申请
    SERINE PROTEASE INHIBITOR KAZAL ANTIBODIES 审中-公开
    丝氨酸蛋白酶抑制剂KAZAL抗体

    公开(公告)号：US20140308657A1

    公开(公告)日：2014-10-16

    申请号：US13991943

    申请日：2011-12-07

    申请人： Xuanyong Lu ,  Timothy M. Block

    发明人： Xuanyong Lu ,  Timothy M. Block

    IPC分类号： G01N33/569 ,  C07K16/38

    CPC分类号： G01N33/56983 ,  C07K16/38 ,  C07K2317/34 ,  C12Q1/37 ,  G01N33/57438 ,  G01N33/5761 ,  G01N33/5767 ,  G01N2800/50

    摘要： This invention describes a relevant etiology of cancer and a novel anti-cancer therapeutic strategy, based on the discovery that a protein named serine protease inhibitor (SPIK/SPINK/PSTI) was up-regulated by hepatitis B and C virus infections consequently suppressing the cell apoptosis. Accordingly, this invention provides an inhibitor of SPIK and/or a technology of suppression of over-expression of SPIK in cells. The inhibitors include: 1) chemical compounds, which can inhibit SPIK transcripts, protein activity, and gene expression, 2) SPIK siRNA (RNAi gene silence or dsRNA of SPIK, 3) DNA anti-sense and anti-SPIK antibody. Further, this invention provides a method of using the inhibitor as an anti-cancer agent to re-instate cancer cell apoptosis (e.g., serine protease dependent cell apoptosis). Also provided is an anti-SPIK antibody specific for an epitope comprising the first nine amino acids of intact SPIK. Further, a diagnostic kit is provided comprising at least one antibody specific for an epitope comprising the first nine amino acids of intact SPIK to diagnose patients exhibiting disease symptoms or at risk for developing a disease, wherein the disease is HBV infection, HCV infection, hepatitis, cancer or hepatic cancer.

    摘要翻译： 本发明描述了癌症的相关病因和新型抗癌治疗策略，基于以下发现：称为丝氨酸蛋白酶抑制剂（SPIK / SPINK / PSTI）的蛋白质被乙型和丙型肝炎病毒感染上调，从而抑制细胞 凋亡。 因此，本发明提供了SPIK抑制剂和/或抑制细胞中SPIK过度表达的技术。 抑制剂包括：1）可抑制SPIK转录物，蛋白质活性和基因表达的化合物，2）SPIK siRNA（SPIK的RNAi基因沉默或dsRNA，3）DNA反义和抗SPIK抗体。 此外，本发明提供了使用该抑制剂作为抗癌剂来重新制备癌细胞凋亡（如丝氨酸蛋白酶依赖性细胞凋亡）的方法。 还提供了对包含完整SPIK的前9个氨基酸的表位特异的抗SPIK抗体。 此外，提供了诊断试剂盒，其包含至少一种特异于包含完整SPIK的前九个氨基酸的表位的抗体，以诊断表现出疾病症状或处于发展疾病的风险的患者，其中所述疾病是HBV感染，HCV感染，肝炎 ，癌症或肝癌。

    Iminosugar compounds with antiflavirus activity
    29.
    发明授权
    Iminosugar compounds with antiflavirus activity 有权
    具有抗病毒活性的Iminosugar化合物

    公开(公告)号：US08097728B2

    公开(公告)日：2012-01-17

    申请号：US12112694

    申请日：2008-04-30

    申请人： Baohua Gu ,  Timothy M. Block ,  Robert M. Moriarty ,  Mahendra N. Deshpande ,  Rajendra C. Shah

    发明人： Baohua Gu ,  Timothy M. Block ,  Robert M. Moriarty ,  Mahendra N. Deshpande ,  Rajendra C. Shah

    IPC分类号： C12N9/99 ,  A61P31/14 ,  C07D211/40

    CPC分类号： C07D211/44

    摘要： An anti-viral compounds effective against viruses belonging to the Flaviviridae family, wherein the anti-viral compounds are 1,5-dideoxy-1,5-imino-D-glucitol derivative compounds having the general formula (I) wherein R2, R3, R4 and R5 are the same or different and are selected from the group consisting of hydrogen, acyl, benzyl, alkyl, aryl, sulfonyl, phosphonyl, silyl, R6 is at least one of alkyl or branched alkyl, heteroalkyl or aryl, R6′ is a bridging group selected from at least one of bicycle[2.2.1]heptyl, bicycle[3.2.1]octyl, oxa analogs, admonyl and cubyl, n′=2-10, n″=1-10, enantiomers and stereoisomers of said compounds and physiologically acceptable salts or solvates of said compounds, enantiomer or stereoisomer.

    摘要翻译： 一种对属于黄病毒科的病毒有效的抗病毒化合物，其中抗病毒化合物是具有通式（I）的1,5-二脱氧-1,5-亚氨基-D-葡萄糖醇衍生物化合物，其中R2，R3， R4和R5相同或不同，选自氢，酰基，苄基，烷基，芳基，磺酰基，膦酰基，甲硅烷基，R6是烷基或支链烷基，杂烷基或芳基中的至少一个，R6'是 选自自行车[2.2.1]庚基，自行车[3.2.1]辛基，氧杂类似物，亚丁基和立方中的至少一种的桥连基团，n'= 2-10，n“= 1-10，对映体和立体异构体 所述化合物和所述化合物的生理学上可接受的盐或溶剂化物，对映异构体或立体异构体。