公开(公告)号：WO2011139695A3

公开(公告)日：2013-05-16

申请号：PCT/US2011033955

申请日：2011-04-26

申请人： ISIS PHARMACEUTICALS INC ,  ALNYLAM PHARMACEUTICALS INC ,  PRAKASH THAZHA P ,  SETH PUNIT P ,  MANORHARAN MUTHIAH ,  SWAYZE ERIC E ,  RAJEEV KALLANTHOTTATHIL G ,  ZLATEV IVAN

发明人： PRAKASH THAZHA P ,  SETH PUNIT P ,  MANORHARAN MUTHIAH ,  SWAYZE ERIC E ,  RAJEEV KALLANTHOTTATHIL G ,  ZLATEV IVAN

IPC分类号： C07H19/10

CPC分类号： C07H19/10 ,  C12N15/113

摘要： Provided herein are modified 5' diphosphate nucleosides and oligomeric compounds prepared therefrom. More particularly, modified 5' diphosphate nucleosides are provided that can be further modified at the 2' and 5' positions. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. The oligomeric compounds are also expected to be useful as primers and probes in diagnostic applications.

摘要翻译： 本文提供修饰的5'二磷酸核苷和由其制备的低聚化合物。 更具体地，提供修饰的5'-二磷酸核苷，其可以在2'和5'位置进一步修饰。 在一些实施方案中，预期本文提供的寡聚化合物与靶RNA的一部分杂交，导致靶RNA的正常功能丧失。 还预期寡聚化合物可用作诊断应用中的引物和探针。

公开(公告)号：WO2013022967A1

公开(公告)日：2013-02-14

申请号：PCT/US2012/049989

申请日：2012-08-08

申请人： ISIS PHARMACEUTICALS, INC. ,  OESTERGAARD, Michael ,  PRAKASH, Thazha, P. ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

发明人： OESTERGAARD, Michael ,  PRAKASH, Thazha, P. ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

IPC分类号： C12N15/113 ,  A61K31/712

CPC分类号： C12N15/113 ,  C12N15/111 ,  C12N2310/11 ,  C12N2310/312 ,  C12N2310/3125 ,  C12N2310/315 ,  C12N2310/316 ,  C12N2310/321 ,  C12N2310/3231 ,  C12N2310/3341 ,  C12N2310/341 ,  C12N2310/351 ,  C12N2320/34 ,  C12N2310/3525

摘要： The present invention provides gapped oligomeric compounds comprising at least one 5'- substituted P-D-2'-deoxyribonucleoside in the gap region. Certain such gapped oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited to, nucleic acids in a cell. The oligomeric compounds provided herein have improved properties such as selectivity, potency and improved proinflammatory profile. In certain embodiments, hybridization results in modulation of the amount of activity or expression of the target nucleic acid in a cell.

摘要翻译： 本发明提供了间隙区域中包含至少一个5'-取代的P-D-2'-脱氧核糖核苷酸的间隙低聚化合物。 某些这样的有效的低聚化合物可用于与互补核酸杂交，包括但不限于细胞中的核酸。 本文提供的寡聚化合物具有改进的性质，例如选择性，效力和改善的促炎症状。 在某些实施方案中，杂交导致细胞中靶核酸的活性或表达量的调节。

公开(公告)号：WO2011139702A2

公开(公告)日：2011-11-10

申请号：PCT/US2011/033968

申请日：2011-04-26

申请人： ISIS PHARMACEUTICALS, INC. ,  PRAKASH, Thazha, P. ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

发明人： PRAKASH, Thazha, P. ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

CPC分类号： C07H21/00 ,  C07H19/067 ,  C07H19/10 ,  C07H19/167 ,  C07H19/20 ,  C07H21/02 ,  C12N15/113 ,  C12N15/1135 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/31 ,  C12N2310/315 ,  C12N2310/318 ,  C12N2310/321 ,  C12N2310/322 ,  C12N2310/3231 ,  C12N2310/345 ,  C12N2310/346 ,  C12N2320/30 ,  C12N2320/51

摘要： The present invention provides modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

摘要翻译： 本发明提供修饰的核苷，其类似物和由其制备的低聚化合物。 更具体地，本发明提供了修饰的核苷及其类似物，其可用于掺入寡聚化合物的末端。 这样的低聚化合物也可以包含在双链组合物中。 在一些实施方案中，预期本文提供的寡聚化合物与靶RNA的一部分杂交，导致靶RNA的正常功能丧失。

公开(公告)号：WO2011123621A2

公开(公告)日：2011-10-06

申请号：PCT/US2011/030695

申请日：2011-03-31

申请人： ALNYLAM PHARMACEUTICALS INC. ,  ISIS PHARMACEUTICALS, INC. ,  REJEEV, Kallanthottathil, G. ,  MANOHARAN, Muthiah ,  SWAYZE, Eric, E. ,  PRAKASH, Thazha, P.

发明人： REJEEV, Kallanthottathil, G. ,  MANOHARAN, Muthiah ,  SWAYZE, Eric, E. ,  PRAKASH, Thazha, P.

IPC分类号： A61K48/00

CPC分类号： C12N15/113 ,  A61K48/00 ,  C07H19/06 ,  C07H19/067 ,  C07H19/16

摘要： The present invention provides nucleosides of formula (1) and oligonucleotides comprising at least on nucleoside of formula (2):Formula (1) and Formula (2). Another aspect of the invention relates to a method of inhibiting the expression of a gene in call, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.

摘要翻译： 本发明提供式（1）的核苷和至少包含式（2）核苷的寡核苷酸：式（1）和式（2）。 本发明的另一方面涉及一种抑制基因表达的方法，所述方法包括（a）使本发明的寡核苷酸与细胞接触; 和（b）将来自步骤（a）的细胞维持足以获得靶基因的mRNA降解的时间。

公开(公告)号：WO2011115818A1

公开(公告)日：2011-09-22

申请号：PCT/US2011/027960

申请日：2011-03-10

申请人： ISIS PHARMACEUTICALS, INC. ,  MIGAWA, Michael, T. ,  PRAKASH, Thazha, P. ,  ALLERSON, Charles ,  BHAT, Balkrishen ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

发明人： MIGAWA, Michael, T. ,  PRAKASH, Thazha, P. ,  ALLERSON, Charles ,  BHAT, Balkrishen ,  SETH, Punit, P. ,  SWAYZE, Eric, E.

IPC分类号： C07H19/073 ,  C07H21/04 ,  C07H19/173 ,  C12N15/113

CPC分类号： C07H19/073 ,  C07H19/173 ,  C07H21/04 ,  C12N15/111 ,  C12N2310/3231

摘要： Provided herein are novel 5'-( S )-CH 3 substituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the furanose ring of each of the novel 5'-( S )-CH 3 substituted bicyclic nucleosides includes a 2' to 4' bridging group. The 5'-( S )-CH 3 substituted bicyclic nucleosides are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as for example increasing the binding affinity. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

摘要翻译： 本文提供了新的5' - （S）-CH 3取代的双环核苷，由其制备的低聚化合物和使用低聚化合物的方法。 更具体地，每个新的5' - （S）-CH 3取代的双环核苷的呋喃糖环包括2'至4'桥连基团。 预期5' - （S）-CH 3取代的双环核苷可用于增强所掺入的寡聚化合物的一种或多种性质，例如增加结合亲和力。 在某些实施方案中，本文提供的寡聚化合物与靶RNA的一部分杂交，导致靶RNA的正常功能丧失。

公开(公告)号：WO2009023855A2

公开(公告)日：2009-02-19

申请号：PCT/US2008073379

申请日：2008-08-15

申请人： ISIS PHARMACEUTICALS INC ,  ALLERSON CHARLES ,  BHAT BALKRISHEN ,  PRAKASH THAZHA P ,  SWAYZE ERIC E ,  SIWKOWSKI ANDREW M ,  SETH PUNIT P

发明人： ALLERSON CHARLES ,  BHAT BALKRISHEN ,  PRAKASH THAZHA P ,  SWAYZE ERIC E ,  SIWKOWSKI ANDREW M ,  SETH PUNIT P

IPC分类号： C12N15/11

CPC分类号： C12N15/113 ,  C07H19/10 ,  C07H19/20 ,  C07H21/00 ,  C12N15/111 ,  C12N2310/323 ,  C12N2320/51

摘要： The present disclosure describes tetrahydropyran nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, tetrahydropyran nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

摘要翻译： 本公开描述了四氢吡喃核苷类似物，由其制备的寡聚化合物以及使用该寡聚化合物的方法。 更具体地说，提供了具有一个或多个手性取代基的四氢​​吡喃核苷类似物，其可用于增强寡聚化合物的性质，包括核酸酶抗性和结合亲和力。 在一些实施方案中，本文提供的寡聚化合物与靶RNA的一部分杂交，导致靶RNA的正常功能丧失。

公开(公告)号：WO2005121371A2

公开(公告)日：2005-12-22

申请号：PCT/US2005/019219

申请日：2005-06-02

申请人： ISIS PHARMACEUTICALS, INC. ,  BHAT, Balkrishen ,  PRAKASH, Thazha, P. ,  DANDE, Prasad ,  ALLERSON, Charles ,  GRIFFEY, Richard ,  SWAYZE, Eric, E.

发明人： BHAT, Balkrishen ,  PRAKASH, Thazha, P. ,  DANDE, Prasad ,  ALLERSON, Charles ,  GRIFFEY, Richard ,  SWAYZE, Eric, E.

IPC分类号： C12Q1/68

CPC分类号： C12N15/113 ,  C07H21/02 ,  C12N15/111 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/32 ,  C12N2310/321 ,  C12N2310/322 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2320/30 ,  C12N2320/51 ,  C12N2310/3521

摘要： The present invention provides douse stranded compositions wherein each strand is modified to have a motif defined by positioning of ß-D-ribonucleosides and sugar modified nucleosides. More particularly, the present compositions comprise one strand having a gapped motif and another strand having a gapped motif, a hemimer motif, a blockmer motif, a fully modified motif, a positionally modified motif or an alternating motif. At least one of the strands has complementarity to a nucleic acid target. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In some embodiments, the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. The present invention also provides methods for modulating gene expression.

摘要翻译： 本发明提供了辫子组合物，其中每条链被修饰为具有通过定位β-D-核糖核苷和糖修饰核苷定义的基序。 更具体地，本发明的组合物包含一个具有间隙基序的链，另一个链具有间隙基序，半缩体基序，封闭基序，完全修饰的基序，位置修饰的基序或交替基序。 至少一条链与核酸靶具有互补性。 该组合物可用于靶向选定的核酸分子并调节一个或多个基因的表达。 在一些实施方案中，本发明的组合物与靶RNA的一部分杂交导致靶RNA的正常功能丧失。 本发明还提供了调节基因表达的方法。

公开(公告)号：WO2004041924A3

公开(公告)日：2005-05-19

申请号：PCT/US0335137

申请日：2003-11-04

申请人： ISIS PHARMACEUTICALS INC ,  BAKER BRENDA F ,  ELDRUP ANNE B ,  MANOHARAN MUTHIAH ,  BHAT BALKRISHEN ,  GRIFFEY RICHARD ,  SWAYZE ERIC E ,  CROOKE STANLEY T ,  PRAKASH THAZHA P

发明人： BAKER BRENDA F ,  ELDRUP ANNE B ,  MANOHARAN MUTHIAH ,  BHAT BALKRISHEN ,  GRIFFEY RICHARD ,  SWAYZE ERIC E ,  CROOKE STANLEY T ,  PRAKASH THAZHA P

IPC分类号： A01N43/04 ,  A61K31/70 ,  A61K48/00 ,  C07H21/02 ,  C07H21/04 ,  C08L20060101 ,  C12N15/113 ,  C12Q1/68 ,  C12N15/87

CPC分类号： C12N15/1135 ,  A61K31/70 ,  C07H21/04 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/318 ,  C12N2310/3181 ,  C12N2310/3183 ,  C12N2310/322 ,  C12N2310/323 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2310/53

摘要： Oligomer compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capble of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes at least two nucleoside having a modified non-phosphorous-containing internucleoside linkage. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least two nucleosides of the oligomer has a modified non-phosphorous-containing internucleoside linkage.

摘要翻译： 提供包含第一和第二寡聚物的低聚物组合物，其中至少一部分第一寡聚体能够与至少一部分第二寡聚物杂交，至少一部分第一寡聚体与所选择的寡核苷酸杂交互补和杂交 靶核酸，并且第一或第二寡聚体中的至少一个包含至少两个具有修饰的含有非磷的核苷间键的核苷。 还提供低聚物/蛋白质组合物，其包含与选定的靶核酸互补并且能够与选定的靶核酸杂交的寡聚体和至少一种包含至少一部分RNA诱导的沉默复合物（RISC）的蛋白质，其中至少两个核苷 低聚物具有经修饰的不含磷的核苷间键。

公开(公告)号：WO2004044134A2

公开(公告)日：2004-05-27

申请号：PCT/US2003/035067

申请日：2003-11-04

申请人： ISIS PHARMACEUTICALS, INC. ,  BAKER, Brenda, F. ,  ELDRUP, Ann, B. ,  MANOHARAN, Muthiah ,  BHAT, Balkrishen ,  GRIFFEY, Richard ,  SWAYZE, Eric, E. ,  CROOKE, Stanley, T. ,  PRAKASH, Thazha, P.

发明人： BAKER, Brenda, F. ,  ELDRUP, Ann, B. ,  MANOHARAN, Muthiah ,  BHAT, Balkrishen ,  GRIFFEY, Richard ,  SWAYZE, Eric, E. ,  CROOKE, Stanley, T. ,  PRAKASH, Thazha, P.

IPC分类号： C12N

CPC分类号： C12N15/1135 ,  C07H21/02 ,  C07H21/04 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/31 ,  C12N2310/311 ,  C12N2310/312 ,  C12N2310/313 ,  C12N2310/314 ,  C12N2310/315 ,  C12N2310/316 ,  C12N2310/319 ,  C12N2310/321 ,  C12N2310/3341 ,  C12N2310/335 ,  C12N2310/341 ,  C12N2310/345 ,  C12N2310/346 ,  C12N2310/3517 ,  C12N2310/53 ,  C12N2310/3525 ,  C12N2310/3521

摘要： Oligonucleotide compositions comprising first and second oligonucleotides are provided wherein at least a portion of the first oligonucleotide is capable of hybridizing with at least a portion of the second oligonucleotide, at least a portion of the first oligonucleotide is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligonucleotides includes at least one nucleotide having a modified phosphorous-containing internucleoside linkage. Oligonucleotide/protein compositions are also provided comprising an oligonucleotide complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleotide of the oligonucleotide has a modified phosphorous-containing internucleoside linkage.

摘要翻译： 提供了包含第一和第二寡核苷酸的寡核苷酸组合物，其中至少一部分第一寡核苷酸能够与至少一部分第二寡核苷酸杂交，第一寡核苷酸的至少一部分与选定的 靶核酸，并且第一或第二寡核苷酸中的至少一个包含至少一个具有修饰的含磷核苷间键的核苷酸。 还提供了寡核苷酸/蛋白质组合物，其包含与选定的靶核酸互补并且能够与选定的靶核酸杂交的寡核苷酸和至少一种包含至少一部分RNA诱导的沉默复合物（RISC）的蛋白质，其中至少一个核苷酸 寡核苷酸具有修饰的含磷核苷键。

公开(公告)号：WO2003004603A3

公开(公告)日：2003-01-16

申请号：PCT/US2002/020940

申请日：2002-07-01

申请人： ISIS PHARMACEUTICALS, INC. ,  PRAKASH, Thazha, P. ,  MANOHARAN, Muthiah

发明人： PRAKASH, Thazha, P. ,  MANOHARAN, Muthiah

IPC分类号： C12Q1/68

摘要： 2'- O -(2-Methylthioethyl), has been incorporated into oligonucleotides and evaluated for antisense properties in comparison with the known 2'- O -(2-methoxyethyl)2'- O -MOE modification. The 2'- O -MOE modified oligonucleotides exhibit improved binding to human serum albumin compared with the 2'- O -MOE modified oligonucleotides and maintain high binding affinity to target RNA.