Chimeric oligomeric compounds comprising alternating regions of northern and southern conformational geometry

Abstract

The present invention relates to novel chimeric oligomeric compounds having a plurality of alternating regions having either RNA like having northern or 3′-endo conformational geometry (3′-endo regions) or DNA like having southern or C2′-endo/O4′-endo conformational geometry. The oligomeric compounds of the present invention have shown reduction in mRNA levels in multiple in vitro and in vivo assay systems and are useful, for example, for investigative and therapeutic purposes.

1 - 67 . (canceled) 
     
     
         68 . A chimeric oligomeric compound comprising from about 5 to about 80 linked nucleosides, wherein the chimeric oligomeric compound is divided into at least 5 separate regions, wherein each of the regions is a continuous sequence from 1 to about 5 nucleosides each comprising a 3′-endo sugar conformational geometry or a continuous sequence of from 1 to about 5 2′-deoxyribonucleosides, and wherein each of the regions comprising from 1 to about 5 2′-deoxyribonucleosides is internally located between two of the regions comprising 1 to about 5 nucleosides each comprising a 3′-endo sugar conformational geometry or at one of the 3′ or 5′-termini. 
     
     
         69 . The compound of  claim 68  comprising 5 separate regions. 
     
     
         70 . The compound of  claim 68  comprising 7 separate regions. 
     
     
         71 . The compound of  claim 68  comprising 9 separate regions. 
     
     
         72 . The compound of  claim 68  comprising 11 separate regions. 
     
     
         73 . The compound of  claim 68  comprising 13 separate regions. 
     
     
         74 . The compound of  claim 68  comprising 15 separate regions. 
     
     
         75 . The compound of  claim 68  comprising 17 separate regions. 
     
     
         76 . The compound of  claim 68  wherein each of the regions is from 1 to 4 nucleosides in length. 
     
     
         77 . The compound of  claim 68  wherein each of the nucleosides comprising a 3′-endo sugar conformational geometry is, independently, a sugar modified nucleoside, a base modified nucleoside, or a nucleoside having one or more modifications that include both the base and the sugar. 
     
     
         78 . The compound of  claim 77  wherein each of the nucleosides comprising a 3′-endo sugar conformational geometry is a sugar modified nucleoside. 
     
     
         79 . The compound of  claim 77  wherein each of the sugar modified nucleosides, independently, comprises a 2′-substituent group. 
     
     
         80 . The compound of  claim 79  wherein each of the 2′-substituent groups is, independently, O(CH 2 ) 2 OCH 3 , O(CH 2 ) 2 SCH 3 , O(CH 2 ) 2 ON(CH 3 ) 2 , O(CH 2 ) 2 —O—(CH 2 ) 2 N(CH 3 ) 2 , OCH 2 C(═O)N(H)CH 3 , OCH 3 , O(CH 2 ) 2 NH 2 , O(CH 2 ) 2 N(CH 3 ) 2 , O(CH 2 ) 3 NH 2 , O(CH 2 ) 3 N(H)CH 3 , CH 2 CH═CH 2 , or O(CH 2 ) 2 S(O)CH 3 . 
     
     
         81 . The compound of  claim 77  wherein at least one of the nucleosides of one of the regions comprising 3′-endo sugar conformational geometry has a bicyclic sugar moiety. 
     
     
         82 . The compound of  claim 81  wherein at least one of the bicyclic sugar moieties is a locked nucleic acid (LNA). 
     
     
         83 . The compound of  claim 68  comprising from about 12 to 30 nucleosides in length. 
     
     
         84 . The compound of  claim 68  comprising from about 15 to 25 nucleosides in length. 
     
     
         85 . The compound of  claim 68  comprising from about 21 to 25 nucleosides in length. 
     
     
         86 . The compound of  claim 68  wherein each of the nucleosides is, independently, linked by phosphodiester or phosphorothioate. 
     
     
         87 . The compound of  claim 68  wherein each of the nucleosides is linked by a phosphorothioate internucleoside linking group.