Abstract: The present invention relates to RNAi molecules, and compositions thereof, comprising a 2? internucleoside linkage connecting the nucleotide at position 1 and the nucleotide at position 2 at the 5? end of the antisense strand. Specifically, the invention relates to single- and double-stranded short interfering nucleic acid (siNA) molecules that are capable of mediating RNA interference comprising 5? modified nucleotides that comprise, among other potential modifications, a 2? internucleoside linkage. The invention further relates to 5? modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

Abstract: This invention relates to a process for introducing two or more 2?-modifications into an RNA, wherein the RNA has a 2?-O substituent containing an alkyl ester functional group on one or more ribose rings of a strand and a 2?-O substituent containing an alkyne functional groups on one or more ribose rings on the same strand. The process comprises a) adding an amine compound to the RNA to form amidation reactions with the alkyl ester functional groups; b) dissolving the modified RNA from step (a) in a solvent to form a solution; and c) adding an organic azide and a copper or ruthenium catalyst to the solution obtained in step (b) to form 2?-azide-alkyne cycloaddition reaction products with the alkyne functional groups.

Abstract: The present invention relates to RNAi molecules, and compositions thereof, comprising a 2? internucleoside linkage connecting the nucleotide at position 1 and the nucleotide at position 2 at the 5? end of the antisense strand. Specifically, the invention relates to single- and double-stranded short interfering nucleic acid (siNA) molecules that are capable of mediating RNA interference comprising 5? modified nucleotides that comprise, among other potential modifications, a 2? internucleoside linkage. The invention further relates to 5? modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

Abstract: The present invention relates to RNAi molecules, and compositions thereof, comprising a 2? internucleoside linkage connecting the nucleotide at position 1 and the nucleotide at position 2 at the 5? end of the antisense strand. Specifically, the invention relates to single- and double-stranded short interfering nucleic acid (siNA) molecules that are capable of mediating RNA interference comprising 5? modified nucleotides that comprise, among other potential modifications, a 2? internucleoside linkage. The invention further relates to 5? modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

Abstract: In an embodiment the instant invention discloses a modular composition comprising 1) an oligonucleotide; 2) one or more linkers, which may be the same or different, selected from Table 1, wherein the linkers are attached to the oligonucleotide at the 2?-position of the ribose rings and/or the terminal 3?- and/or 5?-positions of the oligonucleotide; 3) optionally, one or more peptides, which may be the same or different, selected from SEQ ID NOs: 1-59, wherein the peptides are attached to the linkers; and optionally one or more lipids, solubilizing groups and/or targeting ligands attached to the oligonucleotide.

Abstract: This invention relates to a 2?-modified RNA agent comprising at least one RNA strand containing a 2?-O substituent having an alkyne functional group attaching to the O atom at the 2?-position on one or more ribose rings, wherein the 2?-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5?-end of the RNA strand. This invention also relates to a 2?-modified RNA agent comprising at least one RNA strand containing a 2?-O substituent having a triazole functional group attaching to the O atom at the 2?-position on one or more ribose rings, wherein the 2?-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5?-end of the RNA strand.

Abstract: This invention relates to a 2?-modified RNA agent comprising at least one RNA strand containing a 2?-O substituent having an alkyne functional group attaching to the O atom at the 2?-position on one or more ribose rings, wherein the 2?-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5?-end of the RNA strand. This invention also relates to a 2?-modified RNA agent comprising at least one RNA strand containing a 2?-O substituent having a triazole functional group attaching to the O atom at the 2?-position on one or more ribose rings, wherein the 2?-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5?-end of the RNA strand.

Abstract: In an embodiment the instant invention discloses a modular composition comprising 1) an oligonucleotide; 2) one or more linkers, which may be the same or different, selected from Table 1, wherein the linkers are attached to the oligonucleotide at the 2?-position of the ribose rings and/or the terminal 3?- and/or 5?-positions of the oligonucleotide; 3) optionally, one or more peptides, which may be the same or different, selected from SEQ ID NOs: 1-59, wherein the peptides are attached to the linkers; and optionally one or more lipids, solubilizing groups and/or targeting ligands attached to the oligonucleotide.

Abstract: The present invention relates to RNAi molecules, and compositions thereof, comprising a 2? internucleoside linkage connecting the nucleotide at position 1 and the nucleotide at position 2 at the 5? end of the antisense strand. Specifically, the invention relates to single- and double-stranded short interfering nucleic acid (siNA) molecules that are capable of mediating RNA interference comprising 5? modified nucleotides that comprise, among other potential modifications, a 2? internucleoside linkage. The invention further relates to 5? modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

Abstract: This invention relates to the post-synthetic chemical modifications of RNA at the 2?-position on the ribose rings via orthogonal chemistry involving amidation reactions plus metal catalyzed alkyne-azide cycloaddition (click) reactions.

Abstract: This invention relates to the post-synthetic chemical modification of RNA at the 2?-position on the ribose ring via a copper catalyzed Huisgen cycloaddition (“click” chemistry: Kolb, Sharpless Drug Discovery Today 2003, 8, 1128). The invention 1) avoids complex, tedious multi-step syntheses of each desired modified ribonucleoside; 2) allows diverse chemical modifications using high-fidelity chemistry that is completely orthogonal to commonly used alkylamino, carboxylate and disulfide linker reactivities; 3) allows introduction of functional groups that are incompatible with modern automated solid-phase synthesis of RNA and subsequent cleavage-deprotection steps; 4) allows introduction of functional groups useful as targeting ligands; and 5) enables high-throughput structure-activity relationship studies on chemically modified RNA in 96-well format.

Abstract: In an embodiment the instant invention discloses a modular composition comprising 1) an oligonueleotide; 2) one or more linkers, which may be the same or different, selected from Table 1, wherein the linkers are attached to the oligonucleotide at the 2?-position of the ribose rings and/or the terminal 3?- and/or 5?-positions of the oligonucleotide; 3) optionally, one or more peptides, which may be the same or different, selected from SEQ ID NOs: 1-59, wherein the peptides are attached to the linkers; and optionally one or more lipids, solubilizing groups and/or targeting ligands attached to the oligonucleotide.

Abstract: This invention relates to the post-synthetic chemical modification of RNA at the 2?-position on the ribose ring via a copper catalyzed Huisgen cycloaddition (“click” chemistry: Kolb, Sharpless Drug Discovery Today 2003, 8, 1128). The invention 1) avoids complex, tedious multi-step syntheses of each desired modified ribonucleoside; 2) allows diverse chemical modifications using high-fidelity chemistry that is completely orthogonal to commonly used alkylamino, carboxylate and disulfide linker reactivities; 3) allows introduction of functional groups that are incompatible with modern automated solid-phase synthesis of RNA and subsequent cleavage-deprotection steps; 4) allows introduction of functional groups useful as targeting ligands; and 5) enables high-throughput structure-activity relationship studies on chemically modified RNA in 96-well format.