BIOACTIVE CONJUGATES FOR OLIGONUCLEOTIDE DELIVERY

1 - 44 . (canceled)

45 . A method for selectively delivering a compound to the kidneys of a patient, comprising administering the compound to the patient intravenously, wherein the compound has a structure of Formula I:

wherein:

O is a double-stranded nucleic acid comprising a first oligonucleotide and a second oligonucleotide, wherein:

(1) the first oligonucleotide comprises at least 16 contiguous nucleotides, a 5′ end, a 3′ end, and complementarity to a target;

(2) the second oligonucleotide comprises at least 15 contiguous nucleotides, a 5′ end, a 3′ end, and homology with a target; and

(3) a portion of the first oligonucleotide is complementary to a portion of the second oligonucleotide;

L is a divalent or trivalent linker:

X c is a hydrophobic moiety; and

Z c is a phosphodiester or phosphodiester derivative, or is absent, and wherein X c is a polyunsaturated moiety having three or more double bonds.

46 . A method for treating a disease or disorder of the kidneys in a patient in need of such treatment, comprising administering to the patient a compound having a structure of Formula I:

wherein:

O is a double-stranded nucleic acid comprising a first oligonucleotide and a second oligonucleotide, wherein:

(1) the first oligonucleotide comprises at least 16 contiguous nucleotides, a 5′ end, a 3′ end, and complementarity to a target:

(2) the second oligonucleotide comprises at least 15 contiguous nucleotides, a 5′ end, a 3′ end, and homology with a target: and

(3) a portion of the first oligonucleotide is complementary to a portion of the second oligonucleotide:

L is a divalent or trivalent linker:

X c is a hydrophobic moiety: and

Z c is a phosphodiester or phosphodiester derivative, or is absent.

47 . The method of claim 46 , wherein the disease or disorder is selected from the group consisting of: Glomerulonephritis, Glomerulosclerosis, Nephrolithiasis, Lightwood-Albright syndrome, Polycystic kidney disease, Acute renal failure, Acute renal injury, Chronic kidney disease, Kidney Fibrosis, Diabetic nephropathy, Fabry disease, Fanconi syndrome, Focal segmental glomerulosclerosis, Goodpasture syndrome, Liddle syndrome, Nutcracker syndrome, Peritoneal-renal syndrome, and Renal cell cancer.

48 - 54 . (canceled)

55 . The method of claim 46 , wherein L comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, or a combination thereof; and wherein L is attached to O via the second oligonucleotide.

56 . The method of claim 46 , wherein X c is

(a) selected from the group consisting of fatty acids, steroids, secosteroids, lipids, gangliosides and nucleoside analogs, and endocannabinoids:

(b) has an affinity for low density lipoprotein and/or intermediate density lipoprotein;

(c) is a saturated or unsaturated moiety having fewer than three double bonds;

(d) has an affinity for high density lipoprotein; or

(e) is a polyunsaturated moiety having three or more double bonds.

57 . The method of claim 46 , wherein Z c is selected from the group consisting of:

wherein X is O, S or BH 3 .

58 . The method of claim 46 , wherein X c is selected from the group consisting of: vitamins, neuromodulatory lipids, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, conjugated linolenic acids, and saturated fatty acids.

59 . The method of claim 46 , wherein O comprises one or more chemically-modified nucleotides.

60 . The method of claim 46 , wherein the first or second oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides.

61 . The method of claim 46 , wherein the nucleotides at positions 2 and 14 from the 5′ end of the second oligonucleotide are 2′-methoxy-ribonucleotides.

62 . The method of claim 46 , wherein the nucleotides of the first or second oligonucleotide are connected via phosphodiester or phosphorothioate linkages.

63 . The method of claim 46 , wherein the nucleotides at positions 1 and 2 from the 3′ end or the 5′ end of the second oligonucleotide are connected to adjacent nucleotides via phosphorothioate linkages.

64 . The method of claim 46 , wherein:

(1) the first oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide: and the nucleotides at positions 2 and 14 from the 5′ end of the first oligonucleotide are not 2′-methoxy-ribonucleotides:

(2) the second oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide: and the nucleotides at positions 2 and 14 from the 5′ end of the second oligonucleotide are 2′-methoxy-ribonucleotides:

(3) the nucleotides of the first oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1-6 from the 3′ end, or positions 1-7 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages: and

(4) the nucleotides of the second oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1 and 2 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages.

65 . The method of claim 46 , wherein the first oligonucleotide comprises a moiety X at the 5′ end, wherein X is selected from the group consisting of:

66 . The method of claim 46 . wherein the first oligonucleotide has a structure of Formula (Ia):

X(—K—B—K—A) j (—S—B—S—A) r (—S—B) t —OR   (Ia)

wherein:

X is selected from the proun consisting of

A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;

B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;

K, for each occurrence independently is a phosphodiester or phosphorothioate linker;

S is a phosphorothioate linker;

R is hydrogen, phosphate, vinylphosphonate, or a capping group;

jis 4, 5, 6, or 7;

r is 2 or 3; and

tis 0 or 1.

67 . The method of claim 46 , wherein the first oligonucleotide has a structure of Formula (IIa):

C—L—B(—S—A—S—B) m′ (—P—A—P—B) n′ (—P—A—S—B) q′ (—S—A) r′ (—S—B) t′ —-OR′  (IIa)

wherein:

C—L is:

A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;

B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;

S is a phosphorothioate linker;

P is a phosphodiester linker;

R′ is hydrogen, phosphate, vinylphosphonate, or a capping group;

m′ is 0 or 1;

n′ is 4, 5 or 6;

q′ is 0 or 1;

r′ is 0 or 1; and

t′ is 0 or 1.

68 . The method of claim 46 , wherein the first oligonucleotide has a structure:

X(—S—B—S—A)(—P—B—P—A) 5 (—P—B—S—A)(—S—B—S—A) 2 (—S—B)—OR;

the second oligonucleotide has [[the]] a structure:

C—L—B(—S—A—S—B)(—P—A—P—B) 5 (—S—A)(—S—B)—OR′; and

the compound has a structure of Formula (IIIa):

wherein each | represents a hydrogen bonding interaction.

69 . The method of claim 46 , wherein the first oligonucleotide has a structure:

X(—P—B—P—A) 6 (—P—B—S—A)(—S—B—S—A) 2 (—S—B)—OR;

the second oligonucleotide has a structure:

C—L—B(—S—A—S—B)(—P—A—P—B) 6 —OR; and

the compound has a structure of Formula (IIIb):

wherein each | represents a hydrogen bonding interaction.

70 . The method of claim 57 , wherein when X c is docosahexaenoic acid (DHA), Z c is not Z c1 .

71 . The method of claim 57 , wherein when Z c is Z c1 , X c is not docosahexaenoic acid (DHA).