Linkage modified gapped oligomeric compounds and uses thereof

Abstract

The present invention provides gapped oligomeric compounds. More particularly the gapped oligomeric compounds provided herein comprise at least one modified internucleoside linkage in the gap region. Such gapped oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

1 . A gapped oligomeric compound comprising a contiguous sequence of linked monomer subunits having a gap region located between a 5′-region and a 3′-region wherein the 5′ and 3′-regions each, independently, have from 2 to 8 contiguous RNA-like modified nucleosides, each independently selected from a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety and a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group that each adopt a 3′-endo conformational geometry when put into an oligomeric compound and wherein the gap region has from 8 to 10 contiguous β-D-2′-deoxyribonucleosides and wherein from one to three of the internucleoside linking groups located between β-D-2′-deoxyribonucleosides in the gap region have Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 each X is O or S; 
 each Q is, independently, selected from C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C(═O)OH and CH 2 C(═O)OH; and 
 each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , SJ 1  and OC(═O)J 1 ; 
 each J 1  is, independently, H or C 1 -C 6  alkyl; and 
 wherein each internucleoside linking group other than internucleoside linking groups having Formula I is, independently, a phosphodiester or a phosphorothioate internucleoside linking group. 
 
       
     
     
         2 . The gapped oligomeric compound of  claim 1  having only one internucleoside linking group of Formula I. 
     
     
         3 . The gapped oligomeric compound of  claim 2  wherein the internucleoside linking group of Formula I is located between nucleosides 1 and 2, 2 and 3, or 3 and 4, counting from the 5′ gap junction. 
     
     
         4 . The gapped oligomeric compound of  claim 1  having only two internucleoside linking groups of Formula I. 
     
     
         5 . The gapped oligomeric compound of  claim 4  wherein the internucleoside linking groups of Formula I are located between nucleosides 1 and 3, or 2 and 4, counting from the 5′ gap junction. 
     
     
         6 . The gapped oligomeric compound of  claim 1  wherein each internucleoside linking group other than internucleoside linking groups having Formula I is a phosphorothioate internucleoside linking group. 
     
     
         7 . The gapped oligomeric compound of  claim 1  wherein each monomer subunit comprises a heterocyclic base independently selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. 
     
     
         8 . The gapped oligomeric compound of  claim 1  wherein each Q is, independently, selected from CH 3 , C(═O)OH, CH 2 C(═O)OH, (CH 2 ) 2 OCH 3 , CH═CH 2 , CH 2 CH═CH 2  and C≡CH. 
     
     
         9 . The gapped oligomeric compound of  claim 1  wherein each Q is, independently, selected from C 1 -C 6  alkyl and substituted C 1 -C 6  alkyl. 
     
     
         10 . The gapped oligomeric compound of  claim 9  wherein each Q is, independently, substituted C 1 -C 6  alkyl wherein the substituent group is OJ 1  and J 1  is C 1 -C 6  alkyl. 
     
     
         11 . The gapped oligomeric compound of  claim 9  wherein each Q is CH 3 . 
     
     
         12 . The gapped oligomeric compound of  claim 1  wherein each X is S. 
     
     
         13 . The gapped oligomeric compound of  claim 1  wherein one or more of the RNA-like modified nucleosides each comprising a 2′-substituted furanosyl sugar moiety wherein each 2′-substituent group is, independently, selected from halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 3 )(R 4 ), O(CH 2 ) 2 —ON(R 3 )(R 4 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 3 )(R 4 ), OCH 2 C(═O)—N(R 4 )(R 4 ), OCH 2 C(═O)—N(R 5 )—(CH 2 ) 2 —N(R 3 )(R 4 ) and O(CH 2 ) 2 —N(R 5 )—C(═NR 6 )[N(R 3 )(R 4 )] wherein R 3 , R 4 , R 5  and R 6  are each, independently, H or C 1 -C 6  alkyl. 
     
     
         14 . The gapped oligomeric compound of  claim 13  wherein each 2′-substituent group is independently selected from F, OCH 3 , O(CH 2 ) 2 —OCH 3  and OCH 2 C(═O)—N(H)CH 3 . 
     
     
         15 . The gapped oligomeric compound of  claim 14  wherein each 2′-substituent group is O(CH 2 ) 2 —OCH 3 . 
     
     
         16 . The gapped oligomeric compound of  claim 1  wherein one or more of the RNA-like modified nucleosides comprises a bicyclic furanosyl sugar moiety each having a bridging group independently selected from 4′-(CH 2 )—O-2′, 4′-(CH 2 )—S-2′, 4′-(CH 2 ) 2 —O-2′, 4′-CH(CH 3 )—O-2′, 4′-C—H(CH 2 OCH 3 )—O-2′, 4′-C(CH 3 ) 2 —O-2′, 4′-CH 2 —N(OCH 3 )-2′, 4′-CH 2 —O—N(CH 3 )-2′, 4′-CH 2 —C(H)(CH 3 )-2′ and 4′-CH 2 —C(═CH 2 )-2′. 
     
     
         17 . The gapped oligomeric compound of  claim 18  wherein each bridging group is 4′-CH[(S)—(CH 3 )]—O-2′ or 4′-(CH 2 )—O-2′. 
     
     
         18 . The gapped oligomeric compound of  claim 1  wherein the sugar moiety of each RNA-like modified nucleoside is the same. 
     
     
         19 . The gapped oligomeric compound of  claim 1  comprising at least two different types of RNA-like modified nucleosides wherein the different types of modified nucleosides have at least different modified sugar moieties. 
     
     
         20 . The gapped oligomeric compound of  claim 19  wherein the different types of RNA-like modified nucleosides include 4′-CH[(S)—(CH 3 )]—O-2′ bicyclic nucleosides and 2′-O(CH 2 ) 2 —OCH 3  substituted nucleosides. 
     
     
         21 . The gapped oligomeric compound of  claim 1  wherein the 5′ and 3′-regions each, independently, have from 3 to 6 RNA-like modified nucleosides. 
     
     
         21 . The gapped oligomeric compound of  claim 1  further comprising at least one 5′ or 3′-conjugate group. 
     
     
         23 . A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of  claim 1  wherein said oligomeric compound is complementary to a target RNA.