Sirna Therapeutics, Inc.

Daniel Zewge

Matthew G Stanton

Vasant R Jadhav

Steven L Colletti

Francis Gosselin

Thomas Joseph Tucker

Anthony W Shaw

Zhen Li

David M Tellers

Wonsuk Chang

Yu Yuan

Erin N Guidry

Gregory Copeland

Joseph D Armstrong

Joseph D Iii Armstrong

Gregory T Copeland

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&#x2032; 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&#x2032; modified nucleotides that comprise, among other potential modifications, a 2&#x2032; internucleoside linkage. The invention further relates to 5&#x2032; modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

Short interfering nucleic acid (siNA) molecules containing a 2' internucleoside linkage (3dT)

This invention relates to a process for introducing two or more 2'-modifications into an RNA, wherein the RNA has a 2&#x2032;-O substituent containing an alkyl ester functional group on one or more ribose rings of a strand and a 2&#x2032;-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&#x2032;-azide-alkyne cycloaddition reaction products with the alkyne functional groups.

Post-synthetic orthogonal amidation plus metal catalyzed azide-alkyne cycloaddition click chemistry on siRNA

Short interfering nucleic acid (siNA) molecules containing a 2' internucleoside linkage

This invention relates to a 2'-modified RNA agent comprising at least one RNA strand containing a 2&#x2032;-O substituent having an alkyne functional group attaching to the O atom at the 2&#x2032;-position on one or more ribose rings, wherein the 2&#x2032;-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5&#x2032;-end of the RNA strand. This invention also relates to a 2&#x2032;-modified RNA agent comprising at least one RNA strand containing a 2&#x2032;-O substituent having a triazole functional group attaching to the O atom at the 2&#x2032;-position on one or more ribose rings, wherein the 2&#x2032;-O substituent is located at one or more of positions 2, 3, 4, 7, 8, 9, 10, 11, 13, 14, and 16, from 5&#x2032;-end of the RNA strand.

Post-synthetic chemical modification of RNA at the 2'-position of the ribose ring via 'click' chemistry

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Rahway, NJ, United States of America

Daniel Zewge