Oligoribonucleotides and ribonucleases for cleaving rna

Abstract

Oligomeric compounds including oligoribonucleotides and oligoribonucleosides are provided that have subsequences of 2′-pentoribofuranosyl nucleosides that activate dsRNase. The oligoribonucleotides and oligoribonucleosides can include substituent groups for increasing binding affinity to complementary nucleic acid strand as well as substituent groups for increasing nuclease resistance. The oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics. Also included in the invention are mammalian ribonucleases, i.e., enzymes that degrade RNA, and substrates for such ribonucleases. Such a ribonuclease is referred to herein as a dsRNase, wherein “ds” indicates the RNase's specificity for certain double-stranded RNA substrates. The artificial substrates for the dsRNases described herein are useful in preparing affinity matrices for purifying mammalian ribonuclease as well as non-degradative RNA-binding proteins.

1 . A composition comprising a duplex consisting of a first chemically synthesized oligomeric compound and a second chemically synthesized oligomeric compound, wherein:
 each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently consists of 17 to 25 linked nucleosides;   at least 17 contiguous nucleobases of the first chemically synthesized oligomeric compound are 100% complementary to at least 17 contiguous nucleobases of the second chemically synthesized oligomeric compound and to a target messenger RNA;   at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleosides comprising a 2′-hydroxyl pentofuranosyl sugar moiety;   at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′-fluoro sugar modification; and   the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound are not covalently linked to each other.   
     
     
         2 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         3 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         4 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         9 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently comprises at least one nucleoside comprising a 2′ sugar modification. 
     
     
         10 . The composition of  claim 9  wherein at least one of the 2′ sugar modifications is selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         11 . The compound of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety and at least one nucleoside comprising a 2′ sugar modification. 
     
     
         12 . The compound of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety and at least one nucleoside comprising a 2′ sugar modification. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-fluoro. 
     
     
         16 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-fluoro. 
     
     
         17 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar comprising a 2′-fluoro and at least one nucleoside comprising a sugar comprising a 2′-O-alkyl. 
     
     
         18 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar comprising a 2′-fluoro and at least one nucleoside comprising a sugar comprising a 2′-O-alkyl. 
     
     
         19 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         20 . The composition of  claim 19  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         21 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         22 . The composition of  claim 21  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         23 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides comprising different 2′ sugar modifications. 
     
     
         24 . The composition of  claim 1  wherein the first chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification and the second chemically synthesized oligomeric compound comprises at least one nucleoside that comprises a different 2′ sugar modification. 
     
     
         25 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         26 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         27 . The composition of  claim 1  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         28 . The composition of  claim 27  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         29 . The composition of  claim 1  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         30 . The composition of  claim 29  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         31 . A composition comprising a duplex consisting of a first chemically synthesized oligomeric compound and a second chemically synthesized oligomeric compound, wherein:
 each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently consists of 17 to 25 linked nucleoside subunits;   at least 17 contiguous nucleobases of the first chemically synthesized oligomeric compound are 100% complementary to at least 17 contiguous nucleobases of the second chemically synthesized oligomeric compound and to a target messenger RNA;   each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety;   at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′-fluoro sugar modification; and   the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound are not covalently linked to each other.   
     
     
         32 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         33 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         34 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         35 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         36 . The composition of  claim 35  wherein the at least 4 contiguous nucleosides comprising 2′-hydroxyl pentofuranosyl sugar moieties of the first chemically synthesized oligomeric compound and the at least 4 contiguous nucleosides comprising 2′-hydroxyl pentofuranosyl sugar moieties of the second chemically synthesized oligomeric compound hybridize to each other in the duplex. 
     
     
         37 . (canceled) 
     
     
         38 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         39 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently comprises at least one nucleoside comprising a 2′ sugar modification. 
     
     
         40 . The composition of  claim 39  wherein at least one of the 2′ sugar modifications is selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-fluoro. 
     
     
         44 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-fluoro. 
     
     
         45 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar comprising a 2′-fluoro and at least one nucleoside comprising a sugar comprising a 2′-O-alkyl. 
     
     
         46 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar comprising a 2′-fluoro and at least one nucleoside comprising a sugar comprising a 2′-O-alkyl. 
     
     
         47 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         48 . The composition of  claim 47  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         49 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         50 . The composition of  claim 49  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         51 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides comprising different 2′ sugar modifications. 
     
     
         52 . The composition of  claim 31  wherein the first chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification and the second chemically synthesized oligomeric compound comprises at least one nucleoside that comprises a different 2′ sugar modification. 
     
     
         53 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         54 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         55 . The composition of  claim 31  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         56 . The composition of  claim 31  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         57 . The composition of  claim 31  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         58 . The composition of  claim 31  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         59 . A composition comprising a duplex consisting of a first chemically synthesized oligomeric compound and a second chemically synthesized oligomeric compound, wherein:
 each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently consists of 17 to 25 linked nucleoside subunits;   at least 17 contiguous nucleobases of the first chemically synthesized oligomeric compound are 100% complementary to at least 17 contiguous nucleobases of the second chemically synthesized oligomeric compound and to a target messenger RNA;   at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety;   each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently comprises at least one nucleoside comprising a 2′-fluoro sugar modification; and   the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound are not covalently linked to each other.   
     
     
         60 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         61 . The composition of  claim 59  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         62 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy 
     
     
         67 . (canceled) 
     
     
         68 . The composition of  claim 59  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         69 . The compound of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety and at least one nucleoside comprising a 2′ sugar modification. 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . (canceled) 
     
     
         73 . (canceled) 
     
     
         74 . (canceled) 
     
     
         75 . (canceled) 
     
     
         76 . (canceled) 
     
     
         77 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         78 . The composition of  claim 77  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         79 . The composition of  claim 59  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         80 . The composition of  claim 79  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         81 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides comprising different 2′ sugar modifications. 
     
     
         82 . The composition of  claim 59  wherein the first chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification and the second chemically synthesized oligomeric compound comprises at least one nucleoside that comprises a different 2′ sugar modification. 
     
     
         83 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         84 . The composition of  claim 59  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         85 . The composition of  claim 59  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         86 . The composition of  claim 85  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         87 . The composition of  claim 59  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         88 . The composition of  claim 87  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         89 . A composition comprising a duplex consisting of a first chemically synthesized oligomeric compound and a second chemically synthesized oligomeric compound, wherein:
 each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently consists of 17 to 25 linked nucleoside subunits;   at least 17 contiguous nucleobases of the first chemically synthesized oligomeric compound are 100% complementary to at least 17 contiguous nucleobases of the second chemically synthesized oligomeric compound and to a target messenger RNA;   each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a plurality of nucleoside subunits comprising a 2′-hydroxyl pentofuranosyl sugar moiety;   each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound independently comprises at least one nucleoside comprising a 2′-fluoro sugar modification; and   the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound are not covalently linked to each other.   
     
     
         90 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         91 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a central gap region flanked by at least two wing regions. 
     
     
         92 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         93 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least 4 contiguous nucleosides that comprise 2′-hydroxyl pentofuranosyl sugar moieties. 
     
     
         94 . The composition of  claim 93  wherein the at least 4 contiguous nucleosides comprising 2′-hydroxyl pentofuranosyl sugar moieties of the first chemically synthesized oligomeric compound and the at least 4 contiguous nucleosides comprising 2′-hydroxyl pentofuranosyl sugar moieties of the second chemically synthesized oligomeric compound hybridize to each other in the duplex. 
     
     
         95 . (canceled) 
     
     
         96 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         97 . (canceled) 
     
     
         98 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one 2′ sugar modification selected from, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, polyethylene glycol, and methoxyethoxy. 
     
     
         99 . (canceled) 
     
     
         100 . (canceled) 
     
     
         101 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-fluoro. 
     
     
         102 . (canceled) 
     
     
         103 . (canceled) 
     
     
         104 . (canceled) 
     
     
         105 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides each comprising a sugar comprising a 2′-OCH 3 . 
     
     
         106 . The composition of  claim 105  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         107 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides comprising a sugar comprising a 2′-OCH 3 . 
     
     
         108 . The composition of  claim 107  wherein the 5′ terminal nucleoside of at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises a sugar comprising a 2′-OCH 3 . 
     
     
         109 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least two nucleosides comprising different 2′ sugar modifications. 
     
     
         110 . The composition of  claim 89  wherein the first chemically synthesized oligomeric compound comprises at least one nucleoside comprising a 2′ sugar modification and the second chemically synthesized oligomeric compound comprises at least one nucleoside that comprises a different 2′ sugar modification. 
     
     
         111 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         112 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one nucleoside comprising a sugar surrogate. 
     
     
         113 . The composition of  claim 89  wherein at least one of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         114 . The composition of  claim 113  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         115 . The composition of  claim 89  wherein each of the first chemically synthesized oligomeric compound and the second chemically synthesized oligomeric compound comprises at least one chemically modified internucleoside linkage. 
     
     
         116 . The composition of  claim 115  wherein at least one chemically modified internucleoside linkage is a phosphorothioate linkage.