DICER SUBSTRATE RNA PEPTIDE CONJUGATES AND METHODS FOR RNA THERAPEUTICS
Dicer substrate RNA peptide conjugates comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand, and a peptide, wherein the dicer substrate RNA is conjugated to the peptide, and compositions and methods of use thereof.
1 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO:32 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
2 . The dicer substrate peptide conjugate of claim 1 , wherein the variant is selected from the group consisting of SEQ ID NO:46 PN3846, SEQ ID NO:47 PN3847, SEQ ID NO:48 PN3848, SEQ ID NO:52 PN3889, SEQ ID NO:50 PN3885, SEQ ID NO:54 PN3980, SEQ ID NO:55 PN3981, SEQ ID NO: 51 PN3886, and SEQ ID NO: 53 PN3948.
3 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 34 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
4 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 35 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
5 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 38 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
6 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising a PreS2 translocation motif or a variant thereof, wherein the dsRNA is conjugated to the peptide.
7 . The dicer substrate peptide conjugate of claim 6 , wherein the variant is selected from the group consisting of SEQ ID NO: 34 and SEQ ID NO: 35.
8 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 45 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
9 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a chimeric peptide comprising penatratin or a variant thereof, and a polyarginine comprising at least five arginine residues, wherein the dsRNA is conjugated to the chimeric peptide.
10 . The dicer substrate peptide conjugate of claim 9 , wherein the chimeric peptide is selected from the group consisting of SEQ ID NO: 56 and SEQ ID NO: 57.
11 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 58 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
12 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 59 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
13 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 60 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
14 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 61 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
15 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising SEQ ID NO: 62 or a variant thereof, wherein the dsRNA is conjugated to the peptide.
16 . A dicer substrate peptide conjugate comprising a double stranded ribonucleic acid (dsRNA) having a sense strand and an antisense strand and a double-stranded region of from 25 to 30 base pairs, and a peptide comprising from about 5 to about 100 amino acids, wherein the peptide comprises at least two positively charge amino acid residues, and wherein the dsRNA is conjugated to the peptide.
17 . A pharmaceutical composition comprising a dicer substrate peptide conjugate of claim 1 and one or more carriers.
18 . A method for treating influenza in an animal comprising administering an effective amount of a dicer substrate peptide conjugate of claim 1 to the animal.
19 . A method for treating inflammation associated with TNF-alpha in an animal comprising administering an effective amount of a dicer substrate peptide conjugate of claim 1 to the animal.
20 . The method of claim 19 , wherein the inflammation occurs in arthritis.
21 . The method of claim 19 , wherein the inflammation occurs in psoriasis.
22 . A method for inhibiting expression of a TNF-alpha gene in an animal comprising administering an inhibiting amount of a pharmaceutical composition of a dicer substrate peptide conjugate of claim 1 to the animal.