Modified iRNA agents

An iRNA duplex agent comprising a compound having the structure shown in formula (I′):

• wherein:
• A and B are each independently for each occurrence O, N(RN) or S;
• X and Y are each independently for each occurrence H, a protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a polymer, a nucleotide, annucleoside, —P(Z′)(Z″)O—R1-Q′-R2—OP(Z′″)(Z″″)O-oligonucleotide, or an oligonucleotide, —P(Z′)(Z″)-formula (I), -P(Z′)(Z″)— or -Q-R;
• wherein the oligonucleotide comprises
• (a) a sense strand, wherein said sense strand comprises
• (i) an alternating 2′-fluoro modification and
• (ii) at least one ligand;
• and
• (b) an antisense strand, wherein said antisense strand comprises
• (i) an alternating 2′-halogen modification;
• and
• (ii) a first 5′ terminal antisense nucleotide, wherein said first 5′ terminal antisense nucleotide is phosphorylated at its 5′ carbon position;
• R is L1 or has the structure shown in formula (II)-(V)
• q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different;
• Q and Q′ are independently for each occurrence absent, —(P7-Q7-R7)p-T7- or -T7-Q7-T7′-B-T8′-Q8-T8;
• P2A, P2B, P3A, P3B, P4A, P4B, P5A, P5B, P5C,P7, T2A, T2B, T3A, T3B, T4A, T4B, T5A, T5B,T5C, T7, T7′, T8 and T8′ are each independently for each occurrence absent, CO, NH, O, S,OC(O), NHC(O), CH2, CH2NH or CH2O;
• B is —CH2—N(BL)—CH2—;
• BL is -TB-QB-TB′-Rx;
• Q2A, Q2B, Q3A, Q3B, Q4A, Q4B, Q5A, Q5B, Q5C, Q7, Q8 and QB are independently for each occurrence absent, alkylene, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO2, N(RN), C(R′)═C(R″), C≡C or C(O);
• TB and TB′ are each independently for each occurrence absent, CO, NH, O, S, OC(O), OC(O)O, NHC(O), NHC(O)NH, NHC(O)O, CH2, CH2NH or CH2O;
• Rx is a carbohydrate;
• R1, R2, R2A, R2B, R3A, R3B, R4A, R4B, R5A, R5B, R5C, R7 are each independently for each occurrence absent, NH, O, S, CH2, C(O)O, C(O)NH, NHCH(Ra)C(O), —C(O)—CH(Ra)—NH—, CO, CH═N—O,
• or heterocyclyl;
• L1, L2A, L2B, L3A, L3B, L4A, L4B, L5A, L5B and L5C are each independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide;
• R′ and R″ are each independently H, C1-C6 alkyl, OH, SH or N(RN)2;
• RN is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl or benzyl;
• Ra is H or an amino acid side chain;
• Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S;
• p represents independently for each occurrence 0-20.

A method for delivering a polynucleotide to a specific target in a subject by administering an iRNA duplex agent comprising:

• (a) a sense strand, wherein said sense strand comprises
• (i) an alternating motif with at least 2 different chemically modified nucleotides;
• and
• (ii) one or more carbohydrate ligand;
• and
• (b) an antisense strand, wherein said antisense strand comprises
• (i) an alternating motif with at least 2 different chemically modified nucleotides.