Oligonucleotides comprising a non-phosphate backbone linkage

1. A double-stranded iRNA agent comprising a first strand and a second strand, wherein said first strand and said second strand are represented independently by formula II:

wherein

X 1 is H, —P(O)(OM) 2 , —P(O)(OM)-O—P(O)(OM) 2 , —P(O)(Oalkyl) 2 , —P(O)(Oalkyl)-O—P(O)(Oalkyl) 2 , or -A 6 -[A 7 -(A 5 ) w ] y ;

M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;

R 1 and R 5 represent independently for each occurrence H, alkyl, or halogen;

R 2 and R 3 represent independently for each occurrence H, OH, F, —Oalkyl, —Oallyl, —O(C(R 19 ) 2 ) k OR 19 , —O(C(R 19 ) 2 ) k SR 19 , —O(C(R 19 ) 2 ) k N(R 19 ) 2 , —O(C(R 19 ) 2 ) k C(O)N(R 19 ) 2 , —N(R 19 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C(R 19 ) 2 ) k N((C 1 -C 6 )alkyl) 2 , —O(C(R 19 ) 2 ) k ON((C 1 -C 6 )alkyl) 2 , or —O-A 6 -[A 7 -(A 5 ) w ] y ;

R 4 represents independently for each occurrence H, OH, F, —Oalkyl, —Oallyl, —O(C(R 19 ) 2 ) k OR 19 , —O(C(R 19 ) 2 ) k SR 19 , —O(C(R 19 ) 2 ) k N(R 19 ) 2 , —O(C(R 19 ) 2 ) k C(O)N(R 19 ) 2 , —N(R 19 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C(R 19 ) 2 ) k N((C 1 -C 6 )alkyl) 2 , or —O(C(R 19 ) 2 ) k ON((C 1 -C 6 )alkyl) 2 ;

R 6 , R 7 , and R 9 represent independently for each occurrence H, alkyl, aryl, or aralkyl;

R 8 represents independently for each occurrence alkyl, aryl, or aralkyl;

k represents independently for each occurrence 1, 2, 3, or 4;

n 1 is 1, 2, or 3;

n 2 is an integer in the range of about 15-28, inclusive;

w represents independently for each occurrence 1, 2, or 3 in accord with the rules of valence;

x represents independently for each occurrence 0, 1, 2, or 3;

y represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;

A 1 represents independently for each occurrence:

A 2 represents independently for each occurrence

A 3 represents independently for each occurrence

A 4 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, alkynyl diradical, alkylalkynyl diradical, aminoalkyl diradical, thioether, —C(O)—, —S(O)—, —S(O) 2 —, B 1 C(R) 2 B 2 , B 1 C(R)(B 2 ) 2 , B 1 C(B 2 ) 3 , B 1 N(R)(B 2 ), B 1 N(B 2 ) 2 , or has the formula:

B 1 is a bond between A 3 and A 4 ;

B 2 is a bond between A 4 and A 5 ;

R represents independently for each occurrence hydrogen or alkyl;

m represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;

m 1 represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;

Y represents independently for each occurrence an alkyl diradical, cycloalkyl diradical, heteroalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, heteroaralkyl diradical, —X 2 C(O)X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(NR 6 )X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(S)X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(O)X 2 [C(R 5 ) 2 ] v X 2 C(O)X 2 —,

[C(R 5 ) 2 ] t N(R 6 )O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 6 )N(R 6 )O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )C(O)[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R)CO 2 [C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )C(S)[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )C(S)O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t OC(O)S[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SN(R 7 )CO 2 [C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t —OSi(R 8 ) 2 —O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t —OSO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )SO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SO 2 N(morpholino)-[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 1 ) 2 ] t S[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t —OSO 2 [C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t S[C(R 5 ) 2 ] y —O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t O[C(R 5 ) 2 ] y O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C═NO[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C(O)C(R 5 )═C(R 5 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C(R 5 )═C(R 5 )[C(R 5 ) 2 ] t —, or —[C(R 5 ) 2 ] t X 2 C(O)X 2 [C(R 5 ) 2 ] t —;

X 2 represents independently for each occurrence a bond, O, or N(R 6 );

Z 1 represents independently for each occurrence O, S, or N(R 8 );

Z 2 represents independently for each occurrence alkyl, aryl, aralkyl, B(R 9 ) 3 , —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SM, —Salkyl, —Saryl, —Saralkyl, —[C(R 5 ) 2 ] m N(R 6 ) 2 , —N(R 10 )R 11 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 ) 2 , —N(R 7 )C(O)R 8 , H, —OC(O)R 8 , —CO 2 R 8 , F, Se, —SeR 8 , —(C(R 19 ) 2 ) m OR 19 , —(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m —OR 19 , —N(R 19 )(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, —(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, or -A 8 -[A 9 -(A 5 ) w ] y ;

R 10 and R 11 are independently H, alkyl, or aryl; or R 10 and R 11 taken together form a 3-, 4-, 5-, 6-, or 7-member ring;

R 12 represents independently for each occurrence H, alkyl, or —NHCH 2 CH═CH 2 ;

t represents independently for each occurrence 0, 1, 2, 3, or 4;

v represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;

A 5 represents independently for each occurrence aryl, aralkyl, or the radical of a steroid, bile acid, lipid, folic acid, pyridoxal, B12, riboflavin, biotin, polycyclic compound, crown ether, intercalator, cleaver molecule, protein-binding agent, carbohydrate, or an optionally substituted saturated 5-membered ring;

A 6 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, —C(O)—, —S(O)—, —S(O) 2 —, or is represented by formula:

Z 3 represents independently for each occurrence O or S;

Z 4 represents independently for each occurrence —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SM, —Salkyl, —Saryl, —Saralkyl, —N(R 10 )R 11 , —[C(R 5 ) 2 ] m N(R 6 ) 2 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 ) 2 , —(C(R 19 ) 2 ) m OR 19 , —(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m —OR 19 , —N(R 19 )(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, —(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, aryl, or alkyl;

R 13 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 3 ;

R 14 represents independently for each occurrence alkyl, aryl, aralkyl, acyl, or silyl;

R 15 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, alkylsulfonyl, alkylsulfoxide, arylsulfonyl, arylsulfoxide, or silyl;

R 16 represents independently for each occurrence cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

B 3 is a bond between A 6 and A 7 ;

B 4 is a bond between A 6 and O;

n 3 represents independently for each occurrence an integer in the range of 1-15, inclusive;

n 4 represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;

A 7 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 3 C(R) 2 B 5 , B 3 C(R)(B 5 ) 2 , B 3 C(B 5 ) 3 , B 3 N(R)(B 5 ), B 3 N(B 5 ) 2 , or has the formula:

p represents independently for each occurrence 1, 2, 3, or 4;

B 5 is a bond between A 5 and A 7 ;

A 8 is a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, or is represented by formula:

R 17 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 6 ;

R 18 represents independently for each occurrence H, halogen, alkyl, alkoxyl, —N(R 6 ) 2 , —CN, —[C(R 5 ) 2 ] v C(R 5 )═C(R 5 ) 2 ;

R 19 represents independently for each occurrence H or alkyl;

B 6 is a bond between A 8 and A 9 ;

B 7 is a bond between A 8 and P;

A 9 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 6 C(R) 2 B 8 , B 6 C(R) (B 8 ) 2 , B 6 C(B 8 ) 3 , B 6 N(R)(B 8 ), B 6 N(B 8 ) 2 , or has the formula:

and

B 8 is a bond between A 5 and A 9 ;

provided that at least one occurrence of Y is a P-alkylphosphonate.

2. The compound of claim 1 , wherein A 5 occurs at least once.

3. The compound of claim 2 , wherein A 5 is represented by formula III:

wherein

R 1-III , R 2-III , and R 3-III represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, amino alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R.

4. The compound of claim 3 , wherein R 1-III is methyl, R 2-III is H, and R 3-III is methoxy.

5. The compound of claim 2 , wherein A 5 is represented by formula IV:

wherein

R 1-IV , R 2-IV , and R 3-IV represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, amino alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R.

6. The compound of claim 5 , wherein R 1-IV is methyl, R 2-IV is H, and R 3-IV is isobutyl.

7. The compound of claim 5 , wherein R 3 and R 4 represent independently for each occurrence —NH 2 , —N(H)CH 3 , or —N(CH 3 ) 2 .

8. The compound of claim 1 , wherein the double-stranded iRNA agent is a double-stranded siRNA.

9. The compound of claim 1 , wherein the P-alkylphosphonate is selected from the group consisting of methylphosphonate, isopropylphosphonate, and tert-butylphosphonate.

10. A single-stranded iRNA agent represented by formula V:

wherein

X 1 is H, —P(O)(OM) 2 , —P(O)(OM)-O—P(O)(OM) 2 , —P(O)(Oalkyl) 2 , —P(O)(Oalkyl)-O—P(O)(Oalkyl) 2 , or -A 6 -[A 7 -(A 5 ) w ] y ;

M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;

R 1 and R 5 represent independently for each occurrence H, alkyl, or halogen;

R 2 and R 3 represent independently for each occurrence H, OH, F, —Oalkyl, —Oallyl, —O(C(R 19 ) 2 ) k OR 19 , —O(C(R 19 ) 2 ) k SR 19 , —O(C(R 19 ) 2 ) k N(R 19 ) 2 , —O(C(R 19 ) 2 ) k C(O)N(R 19 ) 2 , —N(R 19 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C(R 19 ) 2 ) k N((C 1 -C 6 )alkyl) 2 , —O(C(R 19 ) 2 ) k ON((C 1 -C 6 )alkyl) 2 , or —O-A 6 -[A 7 -(A 5 ) w ] y ;

R 4 represents independently for each occurrence H, OH, F, —Oalkyl, —Oallyl, —O(C(R 19 ) 2 ) k OR 19 , —O(C(R 19 ) 2 ) k SR 19 , —O(C(R 19 ) 2 ) k N(R 19 ) 2 , —O(C(R 19 ) 2 ) k C(O)N(R 19 ) 2 , —N(R 19 ) 2 , —S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k S(C 1 -C 6 )alkyl, —O(C(R 19 ) 2 ) k O(C(R 19 ) 2 ) k N((C 1 -C 6 )alkyl) 2 , or —O(C(R 19 ) 2 ) k ON((C 1 -C 6 )alkyl) 2 ;

R 6 , R 7 , and R 9 represent independently for each occurrence H, alkyl, aryl, or aralkyl;

R 8 represents independently for each occurrence alkyl, aryl, or aralkyl;

k represents independently for each occurrence 1, 2, 3, or 4;

n 1 is 1, 2, or 3;

n 2 is an integer in the range of about 15-28, inclusive;

w represents independently for each occurrence 1, 2, or 3 in accord with the rules of valence;

x represents independently for each occurrence 0, 1, 2, or 3;

y represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;

A 1 represents independently for each occurrence:

A 2 represents independently for each occurrence:

A 3 represents independently for each occurrence

A 4 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, alkynyl diradical, alkylalkynyl diradical, aminoalkyl diradical, thioether, —C(O)—, —S(O)—, —S(O) 2 —, B 1 C(R) 2 B 2 , B 1 C(R)(B 2 ) 2 , B 1 C(B 2 ) 3 , B 1 N(R)(B 2 ), B 1 N(B 2 ) 2 , or has the formula:

B 1 is a bond between A 3 and A 4 ;

B 2 is a bond between A 4 and A 5 ;

R represents independently for each occurrence hydrogen or alkyl;

m represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;

m 1 represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;

Y represents independently for each occurrence an alkyl diradical, cycloalkyl diradical, heteroalkyl diradical, heterocycloalkyl diradical, alkenyl diradical, alkynyl diradical, aryl diradical, heteroaryl diradical, aralkyl diradical, heteroaralkyl diradical, —X 2 C(O)X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(NR 6 )X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(S)X 2 [C(R 5 ) 2 ] v X 2 —, —X 2 C(O)X 2 -[C(R 5 ) 2 ] v X 2 C(O)X 2 —,

[C(R 5 ) 2 ] t N(R 6 )O[C(R 5 )] t —, —[C(R 5 ) 2 ] t N(R 6 )N(R 6 )O[C(R 5 )] t —, —[C(R 5 ) 2 ] t N(R 7 )C(O)[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R)CO 2 [C(R) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )C(S)[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )C(S)O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t —OC(O)S[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SN(R 7 )CO 2 [C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t OSi(R 8 ) 2 —O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t OSO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )SO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SO 2 N(morpholino)-[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t SO 2 N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 1 ) 2 ] t S[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t —OSO 2 [C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t S[C(R 5 ) 2 ] y —O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t O[C(R 5 ) 2 ] y —O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t O[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t N(R 7 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C═NO[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C(O)C(R 5 )═C(R 5 )[C(R 5 ) 2 ] t —, —[C(R 5 ) 2 ] t C(R 5 )═C(R 5 )[C(R 5 ) 2 ] t —, or —[C(R 5 ) 2 ] t X 2 C(O)X 2 [C(R 5 ) 2 ] t —;

X 2 represents independently for each occurrence a bond, O, or N(R 6 );

Z 1 represents independently for each occurrence O, S, or N(R 8 );

Z 2 represents independently for each occurrence alkyl, aryl, aralkyl, B(R 9 ) 3 , —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SM, —Salkyl, —Saryl, —Saralkyl, —[C(R 5 ) 2 ] m N(R 6 ) 2 , —N(R 10 )R 11 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 ) 2 , —N(R 7 )C(O)R 8 , H, —OC(O)R 8 , —CO 2 R 8 , F, Se, —SeR 8 , —(C(R 19 ) 2 ) m —OR 19 , —(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m OR 19 , —N(R 19 )(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, —(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, or -A 8 -[A 9 -(A 5 ) w ] y ;

R 10 and R 11 are independently H, alkyl, or aryl; or R 10 and R 11 taken together form a 3-, 4-, 5-, 6-, or 7-member ring;

R 12 represents independently for each occurrence H, alkyl, or —NHCH 2 CH═CH 2 ;

t represents independently for each occurrence 0, 1, 2, 3, or 4;

v represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;

A 5 represents independently for each occurrence aryl, aralkyl, or the radical of a steroid, bile acid, lipid, folic acid, pyridoxal, B12, riboflavin, biotin, polycyclic compound, crown ether, intercalator, cleaver molecule, protein-binding agent, carbohydrate, or an optionally substituted saturated 5-membered ring;

A 6 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, —C(O)—, —S(O)—, —S(O) 2 —, or is represented by formula:

Z 3 represents independently for each occurrence O or S;

Z 4 represents independently for each occurrence —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SM, —Salkyl, —Saryl, —-Saralkyl, —N(R 10 )R 11 , —[C(R 5 ) 2 ] m N(R 6 ) 2 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 ) 2 , —(C(R 19 ) 2 ) m OR 19 , —(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m —OR 19 , —N(R 19 )(C(R 19 ) 2 ) m SR 19 , —N(R 19 )(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, —(C(R 19 ) 2 ) m N(R 19 )C(O)alkyl, aryl, or alkyl;

R 13 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 3 ;

R 14 represents independently for each occurrence alkyl, aryl, aralkyl, acyl, or silyl;

R 15 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, alkylsulfonyl, alkylsulfoxide, arylsulfonyl, arylsulfoxide, or silyl;

R 16 represents independently for each occurrence cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

B 3 is a bond between A 6 and A 7 ;

B 4 is a bond between A 6 and O;

n 3 represents independently for each occurrence an integer in the range of 1-15, inclusive;

n 4 represents independently for each occurrence 1, 2, 3, 4, or 5 in accord with the rules of valence;

A 7 represents independently for each occurrence a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 3 C(R) 2 B 5 , B 3 C(R)(B 5 ) 2 , B 3 C(B 5 ) 3 , B 3 N(R)(B 5 ), B 3 N(B 5 ) 2 , or has the formula:

p represents independently for each occurrence 1, 2, 3, or 4;

B 5 is a bond between A 5 and A 7 ;

A 8 is a bond, alkyl diradical, heteroalkyl diradical, alkenyl diradical, aminoalkyl, or is represented by formula:

R 17 represent independently for each occurrence H, alkyl, cycloalkyl, heteroalkyl, aryl, aralkyl, acyl, silyl, or B 6 ;

R 18 represents independently for each occurrence H, halogen, alkyl, alkoxyl, —N(R 6 ) 2 , —CN, —[C(R 5 ) 2 ] v C(R 5 )═C(R 5 ) 2 ;

R 19 represents independently for each occurrence H or alkyl;

B 6 is a bond between A 8 and A 9 ;

B 7 is a bond between A 8 and P;

A 9 is a bond, alkyl diradical, heteroalkyl diradical, —C(O)—, —S(O)—, —S(O) 2 —, B 6 C(R) 2 B 8 , B 6 C(R)(B 8 ) 2 , B 6 C(B 8 ) 3 , B 6 N(R)(B 8 ), B 6 N(B 8 ) 2 , or has the formula:

and

B 8 is a bond between A 5 and A 9 ;

provided that at least one occurrence of Y is a P-alkylphosphonate.

11. The compound of claim 10 , wherein A 5 occurs at least once.

12. The compound of claim 11 , wherein A 5 is represented by formula VI:

wherein

R 1-VI , R 2-VI , and R 3-VI represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, amino alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R.

13. The compound of claim 12 , wherein R 1-VI is methyl, R 2-VI is H, and R 3-VI is methoxy.

14. The compound of claim 11 , wherein A 5 is represented by formula VII:

wherein

R I-VII , R 2-VII , and R 3-VII represent independently for each occurrence H, halogen, amino, hydroxyl, alkyl, alkoxyl, amino alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thiol, thioalkyl, silyl, nitro, nitrile, acyl, acylamino, —COR, or —CO 2 R.

15. The compound of claim 14 , wherein R I-VII is methyl, R 2-VII is H, and R 3-VII is isobutyl.

16. The compound of claim 14 , wherein R 3 and R 4 represent independently for each occurrence —NH 2 , —N(H)CH 3 , or —N(CH 3 ) 2 .

17. The compound of claim 10 , wherein the single-stranded iRNA agent is a single-stranded siRNA.

18. The compound of claim 10 , wherein the single-stranded iRNA agent is a microRNA.

19. The compound of claim 10 , wherein the P-alkylphosphonate is selected from the group consisting of methylphosphonate, isopropylphosphonate, and tert-butylphosphonate.

20. A single-stranded iRNA agent comprising at least one P-alkylphosphonate backbone.

21. The single-stranded iRNA agent of claim 20 , wherein the P-alkylphosphonate backbone is at the 3′ end, the 5′ end, the internucleotide, or a combination thereof.

22. The single-stranded iRNA agent of claim 20 , wherein the P-alkylphosphonate backbone is at the 3′ end.

23. The single-stranded iRNA agent of claim 20 , wherein the P-alkylphosphonate backbone is at the 5′ end.

24. The single-stranded iRNA agent of claim 20 , wherein the P-alkylphosphonate backbone is at both the 3′ end and the 5′ end.

25. The single-stranded iRNA agent of claim 20 , wherein the P-alkylphosphonate is selected from the group consisting of methylphosphonate, isopropylphosphonate, and tert-butylphosphonate.

26. The single-stranded iRNA agent of claim 20 , wherein the single-stranded iRNA agent comprises at least one modified sugar moiety.

27. The single-stranded iRNA agent of claim 20 , wherein the single-stranded iRNA agent is further conjugated to a ligand selected from the group consisting of an aromatic group, aralkyl group, steroid, bile acid, lipid, folic acid, pyridoxal, B12, riboflavin, biotin, polycyclic compound, crown ether, intercalator, cleaver molecule, protein-binding agent, and carbohydrate.

28. An siRNA comprising at least one P-alkylphosphonate backbone.

29. The siRNA of claim 28 , wherein the P-alkylphosphonate backbone is at 3′ end, the 5′ end, the internucleotide, or a combination thereof.

30. The siRNA of claim 28 , wherein the P-alkylphosphonate backbone is at the 3′ end of the sense strand, the 3′ end of the antisense strand, or the 3′ end of both strands.

31. The siRNA of claim 28 , wherein the P-alkylphosphonate backbone is at the 5′ end of the sense strand, the 5′ end of the antisense strand, or the 5′ end of both strands.

32. The siRNA of claim 28 , wherein the P-alkylphosphonate backbone is at the 3′ end of either the sense or antisense stand, and at the 5′ end of either the sense or antisense strand.

33. The siRNA of claim 28 , wherein the P-alkylphosphonate is selected from the group consisting of methylphosphonate, isopropylphosphonate, and tert-butylphosphonate.

34. The siRNA of claim 28 , wherein the siRNA comprises at least one modified sugar moiety.

35. The siRNA of claim 28 , wherein siRNA is further conjugated to a ligand selected from the group consisting of an aromatic group, aralkyl group, steroid, bile acid, lipid, folic acid, pyridoxal, B12, riboflavin, biotin, polycyclic compound, crown ether, intercalator, cleaver molecule, protein-binding agent, and carbohydrate.