siRNAs with vinylphosphonate at the 5′ end of the antisense strand

A nucleic acid for inhibiting expression of a target gene in a cell, comprising at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to at least a portion of RNA transcribed from said target gene to be inhibited,

• and wherein the first strand has a terminal 5′ (E)-vinylphosphonate nucleotide linked by a phosphodiester linkage to the second nucleotide of the first strand and no phosphorothioate internucleotide linkages at the 5′ end of the first strand,
• wherein the second strand of the nucleic acid is conjugated to at least one ligand portion comprising a compound of formula 1:
• [S—X1—P—X2]3-A-X3— (1)
• wherein:
• S represents a saccharide;
• X1 represents C3-C6 alkylene or (—CH2—CH2—O)m(—CH2)2—wherein m is 1, 2, or 3;
• P is a phosphate or modified phosphate;
• X2 is alkylene or an alkylene ether of the formula (—CH2)n—O—CH2—where n=1-6;
• A is a branching unit;
• X3 represents a bridging unit;
• and wherein the nucleic acid is conjugated to X3 via a phosphate or modified phosphate, or
• wherein the second strand of the nucleic acid is conjugated to at least one ligand portion comprising a compound of formula 2:
• [S—X1—P—X2]3-A-X3— (2)
• wherein:
• S represents a saccharide;
• X1 represents C3-C6 alkylene or an ethylene glycol stem (—CH2—CH2—O)m(—CH2)2—
• wherein m is 1, 2, or 3;
• P is a phosphate or modified phosphate;
• X2 is C1-C8 alkylene;
• A is a branching unit;
• X3 is a bridging unit;
• and wherein the nucleic acid is conjugated to X3 via a phosphate or modified phosphate.