Oligonucleotdies having A-DNA form and B-DNA form conformational geometry

Abstract

Modified oligonucleotides containing both A-form conformation geometry and B-from conformation geometry nucleotides are disclosed. The B-form geometry allows the oligonucleotide to serve as substrates for RNase H when bound to a target nucleic acid strand. The A-form geometry imparts properties to the oligonucleotide that modulate binding affinity and nuclease resistance. By utilizing C2′ endo sugars or O4′ endo sugars, the B-form characteristics are imparted to a portion of the oligonucleotide. The A-form characteristics are imparted via use of either 2′-O-modified nucleotides that have 3′ endo geometries or use of end caps having particular nuclease stability or by use of both of these in conjunction with each other.

1 - 36 . (canceled)  
     
     
         37 . An oligonucleotide comprising a plurality of nucleotides and having an A-form region and a B-form region and where one of said nucleotides includes a bicyclic sugar.  
     
     
         38 . An oligonucleotide of  claim 37  wherein said bicyclic sugar includes a further ring locking said one of said nucleosides in a cage-like structure.  
     
     
         39 . An oligonucleotide of  claim 38  wherein said cage-like structure includes C4′.  
     
     
         40 . An oligonucleotide of  claim 38  wherein said cage-like structure locks said one of said nucleotides in a fixed conformation.  
     
     
         41 . An oligonucleotide of  claim 37  further comprising from about 5 to about 50 nucleotides.  
     
     
         42 . An oligonucleotide of  claim 37  further comprising from about 8 to about 30 nucleotides.  
     
     
         43 . An oligonucleotide of  claim 37  further comprising from about 15 to 25 nucleotides.  
     
     
         44 . An oligonucleotide of  claim 37  including a 4′-C-methylene moiety.  
     
     
         45 . An oligonucleotide of  claim 37  including at least one phosphorus based linkage having increased nuclease resistance.  
     
     
         46 . An oligonucleotide of  claim 45  wherein said phosphorus based linkages is a phosphorothioate linkage.  
     
     
         47 . An oligonucleotide comprising a plurality of nucleotides and having an A-form region and a B-form region and where one of said nucleotides comprises a 2′ sugar substitution that locks said sugar in a C3′-endo conformation.  
     
     
         48 . An oligonucleotide of  claim 47  wherein 2′ sugar substitution that locks said sugar in a C3′-endo conformation includes a cage-like structure.  
     
     
         49 . An oligonucleotide of  claim 48  wherein said 2′ sugar substitution that locks said sugar in a C3′-endo conformation includes cage-like structure that extends from C2′.  
     
     
         50 . An oligonucleotide of  claim 47  wherein 2′ sugar substitution that locks said sugar in a C3′-endo conformation forms a part of a bicyclic sugar.  
     
     
         51 . An oligonucleotide of  claim 47  further comprising from about 5 to about 50 nucleotides.  
     
     
         52 . An oligonucleotide of  claim 47  further comprising from about 8 to about 30 nucleotides.  
     
     
         53 . An oligonucleotide of  claim 47  further comprising from about 15 to 25 nucleotides.  
     
     
         54 . An oligonucleotide of  claim 47  including a 4′-C-methylene moiety.  
     
     
         55 . An oligonucleotide of  claim 47  including at least one phosphorus based linkage having increased nuclease resistance.  
     
     
         56 . An oligonucleotide of  claim 55  wherein said phosphorus based linkages is a phosphorothioate linkage.  
     
     
         57 . An oligonucleotide having a plurality of nucleotides and having an A-form region and a B-form region and where one of said nucleotides comprises a ribonucleotide having a ring located on the ribose ring in a cage-like structure.  
     
     
         58 . An oligonucleotide of  claim 57  wherein said cage-like structure physically locks the ribose ring in a fixed conformation.  
     
     
         59 . An ologonucleotide of  claim 57  including a 4′-C-methylene moiety.  
     
     
         60 . An oligonucleotide of  claim 57  further comprising from about 5 to about 50 nucleotides.  
     
     
         61 . An oligonucleotide of  claim 57  further comprising from about 8 to about 30 nucleotides.  
     
     
         62 . An oligonucleotide of  claim 57  further comprising from about 15 to 25 nucleotides.  
     
     
         63 . An oligonucleotide of  claim 57  including at least one phosphorus based linkage having increased nuclease resistance.  
     
     
         64 . An oligonucleotide of  claim 63  wherein said phosphorus based linkages is a phosphorothioate linkage.