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1.发明授权Antisense antiviral compound and method for treating influenza viral infection 有权反义抗病毒化合物及治疗流感病毒感染的方法公开(公告)号：US08357664B2
公开(公告)日：2013-01-22
申请号：US11259434
申请日：2005-10-25
申请人： David A. Stein , Qing Ge , Jianzhu Chen , Patrick L. Iversen , Hong M. Moulton
发明人： David A. Stein , Qing Ge , Jianzhu Chen , Patrick L. Iversen , Hong M. Moulton
IPC分类号： A61K48/00
CPC分类号： C12N15/1131 , C12N2310/3145 , C12N2310/3233 , C12N2310/3513
摘要： The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12-40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5′ or 3′ terminal 25 bases of the negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C; b) the terminal 25 bases of the 3′ terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.
摘要翻译： 本发明提供反义抗病毒化合物及其在抑制正粘病毒科的病毒生长和用于病毒感染治疗中的用途和生产方法。 该化合物特别可用于治疗哺乳动物的流感病毒感染。 反义抗病毒化合物是具有1）核酸酶抗性主链，2）12-40个核苷酸碱基的基本上不带电荷的吗啉代寡核苷酸，和3）长度为至少12个碱基的靶向序列与选自以下的靶区域杂交： ）流感病毒A，流感病毒B和流感病毒C的负义病毒RNA片段的5'或3'末端25个碱基; b）正义cRNA的3'末端的末端25个碱基; 和c）围绕流感病毒mRNA的AUG起始密码子的50个碱基。
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公开(公告)号：US07468418B2
公开(公告)日：2008-12-23
申请号：US10836804
申请日：2004-04-29
CPC分类号： A61K49/0056 , A61K47/64 , A61K49/0043 , A61K49/0054 , C12N15/113 , C12N15/87 , C12N2310/11 , C12N2310/314 , C12N2310/3233 , C12N2310/3513 , C12N2320/32
摘要： Compositions and methods for enhancing delivery of molecules, e.g. biological agents, into cells are described. The composition is a conjugate of the biological agent, preferably a nucleic acid analog having a substantially uncharged backbone, covalently linked to a peptide transporter moiety as described. Conjugation of the peptide transporter to a substantially uncharged nucleic acid analog, such as a morpholino oligomer, is also shown to enhance binding of the oligomer to its target sequence and enhance antisense activity.
摘要翻译： 用于增强分子递送的组合物和方法，例如 描述了生物制剂进入细胞。 组合物是生物制剂的缀合物，优选具有基本上不带电的主链的核酸类似物，其与所述的肽转运蛋白部分共价连接。 还显示肽转运蛋白与基本上不带电的核酸类似物如吗啉代低聚物的缀合增强寡聚物与其靶序列的结合并增强反义活性。
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公开(公告)号：US09572899B2
公开(公告)日：2017-02-21
申请号：US12265499
申请日：2008-11-05
IPC分类号： A61K38/10 , C07K4/00 , A61K38/08 , C07H21/02 , A61K49/00 , A61K47/48 , C12N15/113 , C12N15/87
CPC分类号： A61K49/0056 , A61K47/64 , A61K49/0043 , A61K49/0054 , C12N15/113 , C12N15/87 , C12N2310/11 , C12N2310/314 , C12N2310/3233 , C12N2310/3513 , C12N2320/32
摘要： Compositions and methods for enhancing delivery of molecules, e.g. biological agents, into cells are described. The composition is a conjugate of the biological agent, preferably a nucleic acid analog having a substantially uncharged backbone, covalently linked to a peptide transporter moiety as described. Conjugation of the peptide transporter to a substantially uncharged nucleic acid analog, such as a morpholino oligomer, is also shown to enhance binding of the oligomer to its target sequence and enhance antisense activity.
摘要翻译： 用于增强分子递送的组合物和方法，例如 描述了生物制剂进入细胞。 组合物是生物制剂的缀合物，优选具有基本上不带电的主链的核酸类似物，其与所述的肽转运蛋白部分共价连接。 还显示肽转运蛋白与基本上不带电的核酸类似物如吗啉代低聚物的缀合增强寡聚物与其靶序列的结合并增强反义活性。
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公开(公告)号：US20090082547A1
公开(公告)日：2009-03-26
申请号：US12265499
申请日：2008-11-05
IPC分类号： C07K7/00
CPC分类号： A61K49/0056 , A61K47/64 , A61K49/0043 , A61K49/0054 , C12N15/113 , C12N15/87 , C12N2310/11 , C12N2310/314 , C12N2310/3233 , C12N2310/3513 , C12N2320/32
摘要： Compositions and methods for enhancing delivery of molecules, e.g. biological agents, into cells are described. The composition is a conjugate of the biological agent, preferably a nucleic acid analog having a substantially uncharged backbone, covalently linked to a peptide transporter moiety as described. Conjugation of the peptide transporter to a substantially uncharged nucleic acid analog, such as a morpholino oligomer, is also shown to enhance binding of the oligomer to its target sequence and enhance antisense activity.
摘要翻译： 用于增强分子递送的组合物和方法，例如 描述了生物制剂进入细胞。 组合物是生物制剂的缀合物，优选具有基本上不带电的主链的核酸类似物，其与所述的肽转运蛋白部分共价连接。 还显示肽转运蛋白与基本上不带电的核酸类似物如吗啉代低聚物的缀合增强寡聚物与其靶序列的结合并增强反义活性。
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公开(公告)号：US20090099066A1
公开(公告)日：2009-04-16
申请号：US12217040
申请日：2008-06-30
CPC分类号： C12N15/87 , C07K2319/33 , C12N2810/40
摘要： Cell-penetrating peptides useful for targeting a therapeutic compound to a selected mammalian tissue, methods for their identification, methods of forming conjugate compounds containing such peptides, and conjugates formed thereby are disclosed. The cell-penetrating peptides are 8 to 30 amino acid residues in length and consist of subsequences selected from the group consisting of RXR, RX, RB, and RBR; where R is arginine, B is β-alanine, and each X is independently —C(O)—(CHR1)n—NH—, where n is 4-6 and each R1 is independently H or methyl, such that at most two R1's are methyl. In one embodiment, X is a 6-aminohexanoic acid residue.
摘要翻译： 可用于将治疗化合物靶向选定的哺乳动物组织的细胞穿透肽，其鉴定方法，形成含有此类肽的缀合物的方法和由此形成的缀合物。 细胞穿透肽的长度为8至30个氨基酸残基并由选自RXR，RX，RB和RBR的子序列组成; 其中R是精氨酸，B是β-丙氨酸，每个X独立地是-C（O） - （CHR 1）n -NH-，其中n是4-6，并且每个R 1独立地是H或甲基，使得至多两个 R1是甲基。 在一个实施方案中，X是6-氨基己酸残基。
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公开(公告)号：US08008469B2
公开(公告)日：2011-08-30
申请号：US11941033
申请日：2007-11-15
CPC分类号： A61K31/675 , C07K2319/10 , C12N15/1132 , C12N2310/11 , C12N2810/6054
摘要： A method and conjugate for selectively killing antigen-activated T cells are disclosed. The conjugate is composed of a substantially uncharged antisense compound targeted against the human cFLIP protein, and a reverse TAT (rTAT) polypeptide coupled covalently to the antisense compound. The rTAT polypeptide is effective to produce selective uptake of the conjugate into antigen-activated T cells, relative to the uptake of the conjugate into non-activated T cells. The cFLIP antisense compound causes activation induced cell death (AICD) of activated lymphocytes. The method is useful in treating transplantation rejection and autoimmune conditions.
摘要翻译： 公开了用于选择性杀死抗原活化的T细胞的方法和缀合物。 缀合物由靶向人cFLIP蛋白的基本上不带电的反义化合物和与反义化合物共价偶联的反向TAT（rTAT）多肽组成。 相对于缀合物对非活化T细胞的摄取，rTAT多肽有效产生缀合物选择性吸收抗原激活的T细胞。 cFLIP反义化合物引起活化的淋巴细胞活化诱导的细胞死亡（AICD）。 该方法可用于治疗移植排斥反应和自身免疫病症。
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公开(公告)号：US20120058946A1
公开(公告)日：2012-03-08
申请号：US13219401
申请日：2011-08-26
申请人： Hong M. Moulton , Ryszard Kole
发明人： Hong M. Moulton , Ryszard Kole
CPC分类号： A61K47/48246 , A61K31/7088 , A61K47/64 , C07K2319/33 , C12N15/113 , C12N15/87 , C12N2310/11 , C12N2810/40
摘要： An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is β-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
摘要翻译： 公开了用于治疗强直性营养不良DM1或DM2的反义化合物，增强对心脏和四头肌的反义靶向的方法，以及哺乳动物受试者中治疗DM1或DM2的方法。 寡核苷酸具有8-30个碱基，其中至少8个连续碱基分别与DM1或DM2中的肌营养不良肌群蛋白激酶（DMPK）mRNA的3'UTR区域中的polyCUG或polyCCUG重复序列互补。 与寡核苷酸共轭是具有序列（RXRR（B / X）R）2XB的细胞穿透肽，其中R是精氨酸; B是丙氨酸; 并且每个X是-C（O） - （CH 2）n -NH-，其中n是4-6。 反义化合物有效地选择性地阻断强直肌营养不良动物模型中心肌和四头肌中肌肉样蛋白样蛋白（MBNL1）和/或CUGBP的螯合。
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公开(公告)号：US08741863B2
公开(公告)日：2014-06-03
申请号：US13219401
申请日：2011-08-26
申请人： Hong M. Moulton , Ryszard Kole
发明人： Hong M. Moulton , Ryszard Kole
IPC分类号： C12N15/113 , C07H21/04
CPC分类号： A61K47/48246 , A61K31/7088 , A61K47/64 , C07K2319/33 , C12N15/113 , C12N15/87 , C12N2310/11 , C12N2810/40
摘要： An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is β-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
摘要翻译： 公开了用于治疗强直性营养不良DM1或DM2的反义化合物，增强对心脏和四头肌的反义靶向的方法，以及哺乳动物受试者中治疗DM1或DM2的方法。 寡核苷酸具有8-30个碱基，其中至少8个连续碱基分别与DM1或DM2中的肌营养不良肌群蛋白激酶（DMPK）mRNA的3'UTR区域中的polyCUG或polyCCUG重复序列互补。 与寡核苷酸共轭是具有序列（RXRR（B / X）R）2XB的细胞穿透肽，其中R是精氨酸; B是丙氨酸; 并且每个X是-C（O） - （CH 2）n -NH-，其中n是4-6。 反义化合物有效地选择性地阻断强直肌营养不良动物模型中心肌和四头肌中肌肉样蛋白样蛋白（MBNL1）和/或CUGBP的螯合。
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公开(公告)号：US20100016215A1
公开(公告)日：2010-01-21
申请号：US12493140
申请日：2009-06-26
申请人： Hong M. Moulton , Ryszard Kole
发明人： Hong M. Moulton , Ryszard Kole
CPC分类号： C12N15/113 , A61K31/7088 , A61K47/64 , C07K2319/33 , C12N15/87 , C12N2310/11 , C12N2810/40
摘要： An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R)2XB, where R is arginine; B is β-alanine; and each X is —C(O)—(CH2)n—NH—, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
摘要翻译： 公开了用于治疗强直性营养不良DM1或DM2的反义化合物，增强对心脏和四头肌的反义靶向的方法，以及哺乳动物受试者中治疗DM1或DM2的方法。 寡核苷酸具有8-30个碱基，其中至少8个连续碱基分别与DM1或DM2中的肌营养不良肌群蛋白激酶（DMPK）mRNA的3'UTR区域中的polyCUG或polyCCUG重复序列互补。 与寡核苷酸共轭是具有序列（RXRR（B / X）R）2XB的细胞穿透肽，其中R是精氨酸; B是β-丙氨酸; 并且每个X是-C（O） - （CH 2）n -NH-，其中n是4-6。 反义化合物有效地选择性地阻断强直肌营养不良动物模型中心肌和四头肌中肌肉样蛋白样蛋白（MBNL1）和/或CUGBP的螯合。
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