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    OLIGONUCLEOTIDES COMPRISING A MODIFIED OR NON-NATURAL NUCLEOBASE
    1.
    发明申请
    OLIGONUCLEOTIDES COMPRISING A MODIFIED OR NON-NATURAL NUCLEOBASE 有权
    包含改性或非天然核苷酸的寡核苷酸

    公开(公告)号：US20090281298A1

    公开(公告)日：2009-11-12

    申请号：US12495932

    申请日：2009-07-01

    申请人： Muthiah MANOHARAN ,  Jie XIA ,  Kallanthottathil G. RAJEEV

    发明人： Muthiah MANOHARAN ,  Jie XIA ,  Kallanthottathil G. RAJEEV

    IPC分类号： C07H21/02

    CPC分类号： C07H21/00 ,  A61K31/7115 ,  C07F9/65515 ,  C07F9/65586 ,  C07F9/6561 ,  C07H21/02 ,  Y02A50/385 ,  Y02A50/387 ,  Y02A50/393 ,  Y02A50/395 ,  Y02A50/411 ,  Y02A50/463 ,  Y02A50/465 ,  Y02A50/467

    摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-natural nucleobase. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.

    摘要翻译： 本发明的一个方面涉及包含至少一种非天然核碱基的双链寡核苷酸。 在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吲哚基，硝基吡咯基或硝基咪唑基。 在优选的实施方案中，非天然核碱基是二氟苯甲酰基。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有非天然核碱基。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地含有非天然核碱基。 在某些实施方案中，寡核苷酸链包含至少一个修饰的糖部分。 本发明的另一方面涉及包含至少一种非天然核碱基的单链寡核苷酸。 在优选的实施方案中，非天然核碱基是二氟苯甲酰基。 在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。 在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

    OLIGNUCLEOTIDES COMPRISING A LIGAND TETHERED TO A MODIFIED OR NON-NATURAL NUCLEOBASE
    2.
    发明申请
    OLIGNUCLEOTIDES COMPRISING A LIGAND TETHERED TO A MODIFIED OR NON-NATURAL NUCLEOBASE 有权
    将配对包含在修改或非自然核酸基序列中的OLIGNUCLEOTIDES

    公开(公告)号：US20090312531A1

    公开(公告)日：2009-12-17

    申请号：US12533710

    申请日：2009-07-31

    申请人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV ,  Jie XIA

    发明人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV ,  Jie XIA

    IPC分类号： C07H15/02 ,  C07H21/02

    CPC分类号： C07H21/00 ,  A61K31/7115 ,  C07F9/6561 ,  C07H21/02 ,  C12Q1/6883 ,  Y02A50/385 ,  Y02A50/387 ,  Y02A50/393 ,  Y02A50/395 ,  Y02A50/411 ,  Y02A50/463 ,  Y02A50/465 ,  Y02A50/467

    摘要： One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand tethered to an altered or non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitropyrrolyl, or nitroimidazolyl. In certain embodiments, the ligand is a steroid or aromatic compound. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.

    摘要翻译： 本发明的一个方面涉及包含至少一个与改变的或非天然核碱基连接的配体的双链寡核苷酸。 在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。 在某些实施方案中，配体是类固醇或芳族化合物。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链中只有一条含有与改变的或非天然核碱基连接的配体。 在某些实施方案中，包含双链寡核苷酸的两条寡核苷酸链都独立地包含与改变的或非天然核碱基连接的配体。 在某些实施方案中，寡核苷酸链包含至少一个修饰的糖部分。 本发明的另一方面涉及包含至少一个与改变的或非天然核碱基连接的配体的单链寡核苷酸。 在某些实施方案中，非天然核碱基是二氟苯甲酰基，硝基吡咯基或硝基咪唑基。 在某些实施方案中，配体是类固醇或芳族化合物。 在某些实施方案中，在核苷中天然存在的核糖部分被己糖，多环杂烷基环或环己烯基取代。 在某些实施方案中，寡核苷酸中的至少一个磷酸键被硫代磷酸酯键取代。

    CARBOHYDRATE CONJUGATES AS DELIVERY AGENTS FOR OLIGONUCLEOTIDES
    3.
    发明申请
    CARBOHYDRATE CONJUGATES AS DELIVERY AGENTS FOR OLIGONUCLEOTIDES 有权
    碳氢化合物作为交付剂的交付代理

    公开(公告)号：US20120136042A1

    公开(公告)日：2012-05-31

    申请号：US13326203

    申请日：2011-12-14

    申请人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV ,  Narayanannair K. JAYAPRAKASH ,  Martin MAIER

    发明人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV ,  Narayanannair K. JAYAPRAKASH ,  Martin MAIER

    IPC分类号： A61K31/713 ,  C07K2/00 ,  C12N5/071 ,  C07H21/02

    CPC分类号： A61K47/28 ,  A61K31/70 ,  A61K31/7004 ,  A61K31/7052 ,  A61K31/7088 ,  A61K31/713 ,  A61K47/16 ,  A61K47/22 ,  A61K47/543 ,  A61K47/549 ,  A61K47/60 ,  A61K48/00 ,  C07H21/02 ,  Y02A50/385 ,  Y02A50/411 ,  Y02A50/467 ,  Y02P20/55

    摘要： The present invention provides iRNA agents comprising at least one subunit of the formula (I): wherein: A and B are each independently for each occurrence O, N(RN) or S; X and Y are each independently for each occurrence H, OH, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-Linker-OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, an oligonucleotide, —P(Z′)(Z″)-formula (I), —P(Z′)(Z″)— or -Linker-R; R is LG, -Linker-LG, or has the structure shown below: LG is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide; RN is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S.

    摘要翻译： 本发明提供包含至少一个式（I）亚基的iRNA试剂：其中：A和B各自独立地为O，N（RN）或S; X和Y各自独立地为H，OH，羟基保护基，磷酸基，磷酸二酯基，活化磷酸酯基，活化亚磷酸酯基，亚磷酰胺，固体载体，-P（Z'）（ Z“）O-核苷，-P（Z'）（Z”）O-寡核苷酸，脂质，PEG，类固醇，亲脂性，聚合物，-P（Z'）（Z“）O-Linker- OP（Z'“）（Z”“） - 寡核苷酸，寡核苷酸，-P（Z'）（Z”） - 式（I），-P（Z'）（Z“） - 链接器R R是LG，-Linker-LG，或具有如下结构：每次出现LG独立为碳水化合物，例如单糖，二糖，三糖，四糖，寡糖，多糖; 乙烯基，丙基，异丙基，丁基或苄基各自独立地为N， 和Z'，Z“，Z”“和Z”“各自独立地为O或S.

    PROCESS FOR DESILYLATION OF OLIGONUCLEOTIDES
    7.
    发明申请
    PROCESS FOR DESILYLATION OF OLIGONUCLEOTIDES 有权
    寡核苷酸脱甲酰化方法

    公开(公告)号：US20110196145A1

    公开(公告)日：2011-08-11

    申请号：US13036788

    申请日：2011-02-28

    申请人： Muthiah MANOHARAN ,  Michael E. JUNG ,  Kallanthottathil G. RAJEEV ,  Rajendra K. PANDEY ,  Gang WANG

    发明人： Muthiah MANOHARAN ,  Michael E. JUNG ,  Kallanthottathil G. RAJEEV ,  Rajendra K. PANDEY ,  Gang WANG

    IPC分类号： C07H1/00

    CPC分类号： C07H21/00 ,  C07H21/04 ,  Y02P20/55

    摘要： The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloroamine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.

    摘要翻译： 本发明涉及寡核苷酸合成和纯化的方法和试剂。 本发明的一个方面涉及可用于在寡核苷酸合成中活化亚磷酰胺的化合物。 本发明的另一方面涉及使用本发明的活化剂通过亚磷酰胺方法制备寡核苷酸的方法。 本发明的另一方面涉及硫转移剂。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及通过用本发明的硫转移试剂处理亚磷酸酯制备硫代磷酸酯的方法。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及清除在带有乙腈基保护基团的磷酸酯基团去保护过程中产生的丙烯腈的化合物。 在优选的实施方案中，丙烯腈清除剂是聚合物结合的硫醇。 本发明的另一方面涉及用于将亚磷酸盐氧化成磷酸盐的试剂。 在优选的实施方案中，氧化剂是亚氯酸钠，氯胺或吡啶-N-氧化物。 本发明的另一方面涉及通过退火第一单链寡核苷酸和第二单链寡核苷酸来纯化寡核苷酸以形成双链寡核苷酸的方法; 并对双链寡核苷酸进行色谱纯化。 在优选的实施方案中，色谱纯化是高效液相色谱法。

    PROCESSES AND REAGENTS FOR SULFURIZATION OF OLIGONUCLEOTIDES
    8.
    发明申请
    PROCESSES AND REAGENTS FOR SULFURIZATION OF OLIGONUCLEOTIDES 有权
    用于硫化寡核苷酸的方法和试剂

    公开(公告)号：US20090187027A1

    公开(公告)日：2009-07-23

    申请号：US12351605

    申请日：2009-01-09

    申请人： Muthiah MANOHARAN ,  Michael E. JUNG ,  Kallanthottathil G. RAJEEV ,  Rajendra K. PANDEY ,  Gang WANG

    发明人： Muthiah MANOHARAN ,  Michael E. JUNG ,  Kallanthottathil G. RAJEEV ,  Rajendra K. PANDEY ,  Gang WANG

    IPC分类号： C07F9/28 ,  C07D285/04

    CPC分类号： C07H21/00 ,  C07H21/04 ,  Y02P20/55

    摘要： The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloramine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.

    摘要翻译： 本发明涉及寡核苷酸合成和纯化的方法和试剂。 本发明的一个方面涉及可用于在寡核苷酸合成中活化亚磷酰胺的化合物。 本发明的另一方面涉及使用本发明的活化剂通过亚磷酰胺方法制备寡核苷酸的方法。 本发明的另一方面涉及硫转移剂。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及通过用本发明的硫转移试剂处理亚磷酸酯制备硫代磷酸酯的方法。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及清除在带有乙腈基保护基团的磷酸酯基团去保护过程中产生的丙烯腈的化合物。 在优选的实施方案中，丙烯腈清除剂是聚合物结合的硫醇。 本发明的另一方面涉及用于将亚磷酸盐氧化成磷酸盐的试剂。 在优选的实施方案中，氧化剂是亚氯酸钠，氯胺或吡啶-N-氧化物。 本发明的另一方面涉及通过退火第一单链寡核苷酸和第二单链寡核苷酸来纯化寡核苷酸以形成双链寡核苷酸的方法; 并对双链寡核苷酸进行色谱纯化。 在优选的实施方案中，色谱纯化是高效液相色谱法。

    RNAi Agents Comprising Universal Nucleobases
    9.
    发明申请
    RNAi Agents Comprising Universal Nucleobases 审中-公开
    包含通用核碱基的RNAi试剂

    公开(公告)号：US20110097707A1

    公开(公告)日：2011-04-28

    申请号：US12915529

    申请日：2010-10-29

    申请人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV

    发明人： Muthiah MANOHARAN ,  Kallanthottathil G. RAJEEV

    IPC分类号： C12Q1/70 ,  C07H21/00

    CPC分类号： C07F9/65515 ,  C07F9/65586 ,  C07F9/6561 ,  C07H21/02 ,  C12N15/111 ,  C12N2310/14 ,  C12N2310/331 ,  C12N2320/34

    摘要： One aspect of the present invention relates to an oligonucleotide agent comprising at least one universal nucleobase. In certain embodiments, the universal nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the universal nucleobase is difluorotolyl. In certain embodiments, the oligonucleotide is double-stranded. In certain embodiments, the oligonucleotide is single-stranded. Another aspect of the present invention relates to a method of altering the expression level of a target in the presence of target sequence polymorphism. In a preferred embodiment, the oligonucleotide agent alters the expression of different alleles of a gene. In another preferred embodiment, the oligonucleotide agent alters the expression level of two or more genes. In another embodiment, the oligonucleotide agent alters the expression level of a viral gene from different strains of the virus. In another embodiment, the oligonucleotide agent alters the expression level of genes from different species.

    摘要翻译： 本发明的一个方面涉及包含至少一种通用核碱基的寡核苷酸试剂。 在某些实施方案中，通用核碱基是二氟苯甲酰基，硝基吲哚基，硝基吡咯基或硝基咪唑基。 在优选的实施方案中，通用核碱基是二氟甲苯基。 在某些实施方案中，寡核苷酸是双链的。 在某些实施方案中，寡核苷酸是单链的。 本发明的另一方面涉及在存在靶序列多态性的情况下改变靶的表达水平的方法。 在优选的实施方案中，寡核苷酸试剂改变基因的不同等位基因的表达。 在另一个优选的实施方案中，寡核苷酸试剂改变两个或多个基因的表达水平。 在另一个实施方案中，寡核苷酸试剂改变来自不同病毒株的病毒基因的表达水平。 在另一个实施方案中，寡核苷酸试剂改变来自不同物种的基因的表达水平。