Dual molecular administration of oligonucleotides and peptide-containing conjugates

Description

BACKGROUND OF THE INVENTION

[0001] The delivery of oligonucleotides and other cell membrane impermeable compounds into a living cell is highly restricted by the complex membrane system of the cell. Drugs used in antisense, RNAi, and gene therapies are relatively large hydrophilic polymers and are frequently highly negatively charged. These physical characteristics severely restrict their direct diffusion across the cell membrane. For this reason, the major barrier to polynucleotide therapeutic efficacy is the delivery of the polynucleotide across a cell membrane to the cell cytoplasm or nucleus.

[0002] One approach that has been used to deliver small nucleic acid in vivo has been to attach the nucleic acid to either a small targeting molecule or a lipid or sterol. While some delivery and activity has been observed with these conjugates, the very large nucleic acid dose required with these methods is impractical.

[0003] Considerable amount of literature evidence supports the hypothesis that the major hurdles for oligonucleotide delivery are cell uptake and endosomal escape. Small interfering RNAs (siRNA) can achieve selective knock-down of therapeutic targets by degradation of specific messenger RNA, provided the siRNA reaches the RNA Induced Silencing Complex (RISC) in the cell cytosol. Receptor-targeted siRNA constructs can be taken up by cell surface receptors and accumulate in subcellular vesicles termed endosomes. A small fraction of the siRNA traverses the endosomal membrane to reach the cytosol. The process, termed endosomal escape, is a major barrier to cytosolic delivery and higher potency of siRNA therapeutics.

[0004] There remains a need for additional compositions or or delivery methods that can provide effective in vivo delivery, cell uptake and / or endosomal escape of oligonucleotides.SUMMARY OF THE INVENTION

[0005] The invention is defined by the claims. In particular, the invention concerns: (1) a first composition comprising an oligonucleotide (R) linked to a targeting ligand (G) via a linker (L); and (2) a second composition comprising a peptide (P) linked to a targeting ligand (G) via a linker (L); wherein (R)-(L)-(G) and (P)-(L)-(G) are selected from the following table: Entry (R)-(L)-(G) (P)-(L)-(G) 1TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)2TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1643 (D)3TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1078 (D)4TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1662 (D)5TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1696 (D)6TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1657 (D)7TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1660 (D)8TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)9TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1653 (D)10TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1652 (D)11TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1651 (D)12TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1650 (D)13TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1649 (D)14TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1648 (D)15TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1647 (D)16TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)17TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1645 (D)18TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1633 (D)19TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1632 (D)20TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1634 (D)21TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1631 (D)22TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1697 (D)23TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1702(D)24TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1703 (D)25TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1704 (D)26TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1705 (D)27TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1706 (D)28TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1707 (D)29TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1708 (L)30TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1711 (L)31TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1712 (L)32TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1716 (L)33TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1719 (L)34TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1403 (L)35TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1517 (L)36TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 935 (L)37TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1720 (L)38TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1725 (L)39TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1726 (D)40TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1727 (D)41TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1728(D)42TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1730 (D)43TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1731(D)44TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1733 (D)45TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1734 (D)46TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)47TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)48TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1744 (D)49TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)50TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)51TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)52TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)53TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)54TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)55TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)56TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D) wherein TGN-L-siRNA is SiRNA-II is SiRNA comprising SEQ ID Nos. 1803 and 1805 and SiRNA-III is SiRNA comprising SEQ ID Nos. 1803 and 1806; and TGN-S-S-peptide SEQ ID NO. is: for use as a medicament, wherein the first composition comprising (R)-(L)-(G) and the second composition comprising (P)-(L)-(G) are sequentially administered about 6 minutes to 1 hour apart.

[0006] Embodiments falling outside of this definition do not fall within the scope of the claims.

[0007] References to therapeutic and diagnostic methods herein are to be interpreted as the compositions of the invention for use in such methods (in accordance with Article 53(c) EPC).

[0008] The compositions and administration methods disclosed herein provide unexpected effective in vivo delivery of an oligonucleotide through dual molecular delivery of the oligonucleotide and a peptide containing conjugate which are not covalently linked to each other.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 shows a time course of mRNA KD following different treatments. Sequential dosing with peptide (or sucrose buffer) was dosed 15 min after siRNA. The 5 mg / kg siRNA only group had no peptide or sucrose buffer and was dosed s.c. compared to all other groups dosed via i.v. route. Fig. 1 shows both peptides generated faster mRNA knockdown (KD) compared to siRNA alone (dose matched by i.v. or standard SCE format by s.c.). Figure 2 shows a time course of RISC loading following different treatments. RISC data which shows faster RISC loading for both peptides matches the mRNA KD data. At 72 hr, there is 10 to 20-fold higher RISC loading with DMD compared to 0.5 mg / kg dose of siRNA with buffer (no peptide). With DMD format, there is 3 to 4-fold higher RISC loading compared to a 10X higher dose with standard subQ siRNA format. Figure 3 shows liver siRNA PK. This figure indicates peptide does not influence amount of siRNA in liver over time. It also shows that s.c. injection of 10-fold higher siRNA dose gets more siRNA into liver. DMD can achieve greater RISC loading and mRNA KD with less siRNA in liver. Figure 4 shows a time course of mRNA KD following different treatments. Sequential dosing with peptide (or sucrose buffer) dosed 15 min after siRNA. This figure shows that addition of vinylPmoeT to GS (siRNA-III) generates faster KD compared to siRNA-I. Both siRNAs show faster and greater KD in DMD format compared to 5-fold higher dose of siRNA-III alone. Figure 5 shows a time course of RISC loading following different treatments. This data matches the mRNA KD data, showing the siRNA-III generates faster RISC loading due to addition of vinyl phosphonate. It also shows the rate of RISC loading is much faster when using peptides in DMD format compared to siRNA alone. Figure 6 shows a time course of RISC loading following different treatments. The order of siRNA stability is siRNA-I > siRNA-V > siRNA-VI and the data shows that metabolic stability is critical to siRNA activity. With a highly stable siRNA-I, the timing of peptide dose does not significantly change the activity (within 2 hr before up to 24 hr after siRNA dose). With the moderately stable siRNA-V, peptide dose times within 2 hr (before or after) the siRNA generate a low level of activity (~25% KD). Longer separation times (4-24 hr post-siRNA dose) or more unstable siRNAs (siRNA-VI) both reduced the activity to background levels. Figure 7 shows mRNA KD in monkey liver. The mRNA expression relative to each animal's pre-dose biopsy. Achieved ~50 % KD in non-human primates at 10 mpk of peptide dose. DETAILED DESCRIPTION OF THE INVENTION

[0010] The compositions and administration methods disclosed herein provide effective in vivo delivery of an oligonucleotide through dual molecular delivery of the oligonucleotide and a peptide containing conjugate. The oligonucleotide and the peptide containing conjugate are not covalently linked to each other and can be co-administered or sequentially administered to a subject.

[0011] The use of dual molecular delivery disclosed herein provides the unexpected benefits of effective in vivo cytosolic delivery of the oligonuleotide by directing the oligonucleotide to the site of action of a particular cell. The peptides may function as endosomolytic, cell penetrating and / or fusogenic agents. For example, the co-administered or sequentially administered peptide-containing conjugate helps with membrane translocation of the oligonucleotide and / or targeting of intended cells.

[0012] The oligonucleotide may be used directly as one component of the dual molecular delivery system. Alternatively, it can be attached to a targeting ligand, and optionally through a linker, to form a conjugate before administration. When present, the targeting ligands and / or linkers are attached to the oligonucleotide at different 2'-positions of the ribose rings and / or the terminal 3' and / or 5'-positions of the oligonucleotide.

[0013] For peptide conjugates used herein, an optional linker may be present between each peptide and a targeting ligand. Multiple peptides and / or multiple linkers and ligands may be used in the conjugates.

[0014] In one embodiment, a method for inhibiting expression of a gene of a subject comprises administering: (1) a composition comprising to the subject; wherein: R is an oligonucleotide with the ability to inhibit expression of a gene; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; X is a lipid; P is a peptide selected from Table 2; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0015] In one embodiment, a method for inhibiting expression of a gene of a subject comprises administering: (1) a composition comprising R-(L) a -(G) b to the subject; wherein: R is an oligonucleotide with the ability to inhibit expression of a gene; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0016] In one embodiment, a method for inhibiting expression of a gene of a subject comprises administering to the subject a composition comprising: (1) wherein: R is an oligonucleotide with the ability to inhibit expression of a gene; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; X is a lipid; P is a peptide selected from Table 2; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) (P) c -(L) d -(G) e ; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0017] In one embodiment, a method for inhibiting expression of a gene of a subject comprises administering to the subject a composition comprising: (1) R-(L) a -(G) b ; wherein: R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) (P) c -(L) d -(G) e ; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0018] In one embodiment of the above inhibition methods, R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA.

[0019] In one embodiment, a method for expressing a protein or polypeptide in a subject comprises administering: (1) a composition comprising to the subject; wherein: R is an oligonucleotide with the ability to encode a protein or polypeptide; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; X is a lipid; P is a peptide selected from Table 2; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0020] In one embodiment, a method for expressing a protein or polypeptide in a subject comprises administering: (1) a composition comprising R-(L) a -(G) b to the subject; wherein: R is an oligonucleotide with the ability to encode a protein or polypeptide; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0021] In one embodiment, a method for expressing a protein or polypeptide in a subject comprises administering to the subject a composition comprising: (1) wherein: R is an oligonucleotide with the ability to encode a protein or polypeptide; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; X is a lipid; P is a peptide selected from Table 2; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) (P) c -(L) d -(G) e ; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0022] In one embodiment, a method for expressing a protein or polypeptide in a subject comprises administering to the subject a composition comprising: (1) R-(L) a -(G) b ; wherein: R is an oligonucleotide with the ability to encode a protein or polypeptide; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; and each of a and b is independently 0, 1, 2, 3 or 4; and (2) (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6.

[0023] In one embodiment of the above expression methods, R is an oligonucleotide selected from the group consisting of DNA, RNA, and mRNA.

[0024] In one embodiment of the above methods, R is a ds siRNA or ss siRNA.

[0025] In one embodiment of the above methods, occurance of P is independently selected from Table 2a.

[0026] In one embodiment of the above methods, occurance of P is independently selected from Table 2b.

[0027] In one embodiment of the above methods, each occurance of L is independently selected from Table 3a.

[0028] In one embodiment of the above methods, each occurance of G is independently selected from Table 4a.

[0029] In one embodiment of the above methods, G comprises: wherein Ac is acetyl; wherein each X is independently -O-, -S-, -CH 2 - or -NH-; each n is independently 1, 2, 3, or 4; and the bond with "" indicates the point of attachment.

[0030] In one embodiment of the above methods, G comprises:

[0031] In one embodiment of the above methods, each of a and b is independently 0, 1 or 2; c is 1 or 2; and each of d and e is independently 1, 2 or 3.

[0032] In one embodiment of the above methods, each of a and b is independently 0 or 1; c is 1; and each of d and e is independently 1 or 2.

[0033] In one embodiment of the above methods, each of a and b is 1; c is 1; and each of d and e is 1.

[0034] In one embodiment, a method comprises: (1) administering a composition comprising R-(L) a -(G) b to the subject; wherein: R is an siRNA; L is a linker and each occurance of L is independently selected from Table 3a; G is a targeting ligand and each occurance of G is independently selected from Table 4a; and each of a and b is independently 0, 1 or 2; and (2) administering a composition comprising (P) c -(L) d -(G) e to the subject; wherein: P is a peptide and each occurance of P is independently selected from Table 2b; L is a linker and each occurance of L is independently selected from Table 3a; G is a targeting ligand and each occurance of G is independently selected from Table 4a; and each of c, d and e is independently 1, 2 or 3.

[0035] In one embodiment of the above methods: L of R-(L) a -(G) b is or G of R-(L) a -(G) b is: each of a and b is 1; and (P) c -(L) d -(G) e of composition (2) is: wherein P is a peptide selected from Table 2b; and wherein L of composition (2) is selected from: and

[0036] In one embodiment of the above methods, each L of compositions (1) and (2) is independently

[0037] In one embodiment of the above methods, R-(L) a -(G) b further comprises a lipid.

[0038] In one embodiment of the above methods, R-(L) a -(G) b further comprises a peptide.

[0039] In one embodiment of the above methods, (P) c -(L) d -(G) e further comprises a lipid.

[0040] In one embodiment of the above methods, (P) c -(L) d -(G) e further comprises an oligonucleotide.

[0041] In one embodiment of the above methods, the composition comprising R-(L) a -(G) b and the composition comprising (P) c -(L) d -(G) e are co-administered at the same time. In one embodiment, the two compositions are in the same formulation. In another embodiment, the two compositions are in different formulations.

[0042] In one embodiment of the above methods, the composition comprising (P) c -(L) d -(G) e and the composition comprising R-(L) a -(G) b are sequentially administered about 0.1 hour to 2 hours apart.

[0043] In one embodiment of the above methods, the composition comprising (P) c -(L) d -(G) e and the composition comprising R-(L) a -(G) b are sequentially administered to a subject about 0.1 hour to 24 hours apart. In another embodiment the sequential administrations are about 0.1 hour to 6 hours apart. In another embodiment the sequential administrations are about 0.25 hour to 2 hours apart. In another embodiment the sequential administrations are about 0.25 hour to 1 hour apart. In another embodiment the sequential administrations are about 0.25 hour to 0.5 hour apart. In another embodiment the sequential administrations are about 0.25 hour apart.

[0044] In one embodiment of the above methods, the composition comprising (P) c -(L) d -(G) e is administered about 0.1 hour to 2 hours before the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.1 hour to 1 hour before the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.25 hour to 0.5 hour before the composition comprising R-(L) a -(G) b is administered to a subject.

[0045] In one embodiment of the above methods, the composition comprising (P) c -(L) d -(G) e is administered about 0.1 hour to 24 hours after the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.1 hour to 12 hours after the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.25 hour to 6 hours after the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.25 hour to 2 hours after the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.25 hour to 1 hour after the composition comprising R-(L) a -(G) b is administered to a subject. In another embodiment, the composition comprising (P) c -(L) d -(G) e is administered about 0.25 hour to 0.5 hour after the composition comprising R-(L) a -(G) b is administered to a subject.

[0046] In one embodiment of the above methods, the compositions of oligonucleotide and peptide are dosed either by intravenous (i.v.) or subcutaneous (s.c.) injections. In another embodiment, the compositions are dosed by intravenous (i.v.) injections. In another embodiment, the compositions are dosed by subcutaneous (s.c.) injections.

[0047] In one embodiment of the above methods, the oligonucleotide composition is administered at a dose of 0.1 to 20 mg / kg (mpk). In another embodiment, the oligonucleotide composition is administered at a dose of 0.1 to 10 mpk. In another embodiment, the oligonucleotide composition is administered at a dose of 0.1 to 5 mpk. In another embodiment, the oligonucleotide composition is administered at a dose of 0.1 to 2 mpk. In another embodiment, the oligonucleotide composition is administered at a dose of 0.1 to 1 mpk. In another embodiment, the oligonucleotide composition is administered at a dose of 0.5 mpk.

[0048] In one embodiment of the above methods, the peptide composition is administered at a dose of 0.1 to 500 mpk. In another embodiment, the peptide composition is administered at a dose of 1 to 200 mpk. In another embodiment, the peptide composition is administered at a dose of 1 to 100 mpk. In another embodiment, the peptide composition is administered at a dose of 5 to 60 mpk. In another embodiment, the peptide composition is administered at a dose of 10 to 50 mpk.

[0049] In one embodiment of the above methods, the oligonucleotide composition is administered at a dose of 0.1 to 5 mpk; and the peptide composition is administered at a dose of 1 to 100 mpk

[0050] In one embodiment, a composition for dual molecular delivery of an oligonucleotide and a peptide conjugate comprises: (1) R-(L) a -(G) b ; and (2) (P) c -(L) d -(G) e ; wherein: R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and each of c, d and e is independently 1, 2, 3, 4, 5 or 6.

[0051] In one embodiment of the above composition, each occurance of P is independently selected from Table 2a.

[0052] In one embodiment of the above composition, each occurance of P is independently selected from Table 2b.

[0053] In one embodiment of the above composition, each occurance of L is independently selected from Table 3a.

[0054] In one embodiment of the above composition, each occurance of G is independently selected from Table 4a.

[0055] In one embodiment of the above composition, each of a and b is independently 0, 1 or 2. In another embodiment, each of a and b is 0. In another embodiment, each of a and b is 1.

[0056] In one embodiment of the above composition, each of c, d and e is independently 1, 2 or 3. In another embodiment, each of c, d and e is 1.

[0057] In one embodiment of the above composition: R is an siRNA; each occurance of P is independently selected from Table 2b; each occurance of L is independently selected from Table 3a; each occurance of G is independently selected from Table 4a; each of a and b is independently 0, 1 or 2; c is 1 or 2; and each of d and e is independently 1, 2 or 3.

[0058] In one embodiment of the above composition, G comprises a ligand of the following formula: wherein each X is independently -O-, -S-, -CH 2 - or -NH-; each n is independently 1, 2, 3, or 4; and the bond with "" indicates the point of attachment.

[0059] In another embodiment, G of the above composition comprises a ligand of the following formula:

[0060] In one embodiment of the above composition, each of a and b is independently 0 or 1; c is 1; and each of d and e is 1.

[0061] In one embodiment of the above composition: (1) G of R-(L) a -(G) b is: each of a and b is 1; and (2) (P) c -(L) d -(G) e is: wherein P is a peptide selected from Table 2b; and wherein each L of compositions (1) and (2) is independently selected from: and

[0062] In one embodiment of the oligonucleotide composition, the oligonucleotide is a double stranded siRNA; and G is attached to the guide and / or passenger strand of the siRNA, wherein the point of attachment is at a 2'-position of a ribose ring and / or at a terminal 3' and / or 5'-position.

[0063] In one embodiment, the composition of R-(L) a -(G) b further comprises a lipid or solubilizing agent.

[0064] In one embodiment, the composition of R-(L) a -(G) b further comprises a lipid.

[0065] In one embodiment, the composition of R-(L) a -(G) b further comprises a peptide.

[0066] In one embodiment, the composition of (P) c -(L) d -(G) e further comprises a lipid.

[0067] In one embodiment, the composition of (P) c -(L) d -(G) e further comprises an oligonucleotide.

[0068] In one embodiment, disclosed herein is a method for inhibiting the expression of one or more genes. The method comprises contacting one or more cells with a therapeutically effective amount of an oligonucleotide composition of the invention together with a peptide containing conjugate, wherein the effective amount is an amount that suppresses the expression of the one or more genes. The method can be performed in vitro or ex vivo.

[0069] In one embodiment, disclosed herein is a method for expressing a protein or polypeptide of a gene. The method comprises contacting one or more cells with a therapeutically effective amount of an oligonucleotide composition of the invention together with a peptide containing conjugate, wherein the effective amount is an amount that suppresses the expression of the one or more genes. The method can be performed in vitro or ex vivo.

[0070] The methods and compositions of the invention can be used for the treatment of any disease or disorder known in the art, and for the treatment of any subject, e.g., any animal, any mammal, such as any human. One of ordinary skill in the art will also recognize that the methods and compositions of the invention may be used for the treatment of any disease that would benefit from downregulating or silencing a gene or genes.

[0071] The methods and compositions of the invention may be used with any dosage and / or formulation described herein, or any dosage or formulation known in the art. In addition to the routes of administration described herein, a person skilled in the art will also appreciate that other routes of administration may be used to administer the modular composition of the invention.Oligonucleotide

[0072] An "oligonucleotide" as used herein, is a double stranded or single stranded, unmodified or modified RNA or DNA, including mRNA. Examples of modified RNAs include those which have greater resistance to nuclease degradation than do unmodified RNAs. Further examples include those which have a 2' sugar modification, a base modification, a modification in a single strand overhang, for example a 3' single strand overhang, or, particularly if single stranded, a 5' modification which includes one or more phosphate groups or one or more analogs of a phosphate group. Examples and a further discription of oligonucleotides can be found in WO2009 / 126933.

[0073] In an embodiment, an oligonucleotide is an antisense, miRNA or siRNA. In one embodiment, the siRNA is a double stranded siRNA (ds siRNA). In another embodiment, the siRNA is a single stranded siRNA (ss siRNA). In an embodiment, the oligonuleotide is the passenger strand of an siRNA. In an embodiment, the oligonucleotide is the guide strand of an siRNA. In an embodiment, an oligonucleotide is mRNA.siRNA

[0074] siRNA directs the sequence-specific silencing of mRNA through a process known as RNA interference (RNAi). The process occurs in a wide variety of organisms, including mammals and other vertebrates. Methods for preparing and administering siRNA and their use for specifically inactivating gene function are known. siRNA includes modified and unmodified siRNA. Examples and a further discription of siRNA can be found in WO2009 / 126933.

[0075] A number of exemplary routes of delivery as described in the Example section can be used to administer siRNA to a subject. In addition, the siRNA can be formulated according to any exemplary method known in the art. Examples and a further discription of siRNA formulation and administration can be found in WO2009 / 126933.

[0076] In some embodiments, siRNA sequences shown in Table 1 as well as their unmodified equivalents are suitable for compositions and methods as discribed herein and used in the Example section. Table 1Sequence Code Gene Target Strand Sequence SEQ ID NO siRNA-I CTNNB1passenger1803CTNNB1guide1804siRNA-II CTNNB1passenger1803CTNNB1guide1805siRNA-III CTNNB1passenger1803CTNNB1guide1806siRNA-IV CTNNB1passenger1807CTNNB1guide1806siRNA-V CTNNB1passenger1803CTNNB1guide1808siRNA-VI CTNNB1passenger1803CTNNB1guide1809Note: As used herein, ome = 2' methoxy; flu = 2' fluoro; click = 2' propagyl; iB = inverted abasic; "s" subscript = phosphorothioate; r = 2' ribo; and 6amil = n-hexylamino. Peptides

[0077] For macromolecular drugs and hydrophilic drug molecules, which cannot easily cross bilayer membranes, entrapment in endosomal / lysosomal compartments of the cell is thought to be the biggest hurdle for effective delivery to their site of action. Without wishing to be bound by theory, it is believed that the use of peptides will facilitate oligonucleotide escape from these endosomal / lysosomal compartments or oligonucleotide translocation across a cellular membrane and release into the cytosolic compartment. In certain embodiments, the peptides of the present invention may be polycationic or amphiphilic or polyanionic peptides or peptidomimetics which show pH-dependent membrane activity and / or fusogenicity. A peptidomimetic may be a small protein-like chain designed to mimic a peptide.

[0078] In some embodiments, the peptide is a cell-permeation agent, preferably a helical cell-permeation agent. These peptides are commonly referred to as Cell Penetrating Peptides. See, for example, "Handbook of Cell Penetrating Peptides" Ed. Langel, U.; 2007, CRC Press, Boca Raton, Florida. Preferably, the component is amphipathic. The helical agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. A cell-permeation agent can be, for example, a cell permeation peptide, cationic peptide, amphipathic peptide or hydrophobic peptide, e.g. consisting primarily of Tyr, Trp and Phe, dendrimer peptide, constrained peptide or crosslinked peptide. Examples of cell penetrating peptides include Tat, Penetratin, and MPG. For the present invention, it is believed that the cell penetrating peptides can be a "delivery" peptide, which can carry large polar molecules including peptides, oligonucleotides, and proteins across cell membranes. Cell permeation peptides can be linear or cyclic, and include D-amino acids, "retro-inverso" sequences, non-peptide or pseudo-peptide linkages, peptidyl mimics. In addition the peptide and peptide mimics can be modified, e.g. glycosylated, pegylated, or methylated. Examples and a further discription of peptides can be found in WO2009 / 126933. Synthesis of peptides is well known in the art.

[0079] The peptides may be conjugated through either end or both ends by addition of a cysteine or other thiol containing moiety to the C- or N -terminus. When not functionalized on the N-terminus, peptides may be capped by an acetyl group, or may be capped with a lipid, a PEG, or a targeting moiety. When the C-terminus of the peptides is unconjugated or unfunctionalized, it may be capped as an amide, or may be capped with a lipid, a PEG, or a targeting moiety.

[0080] Suitable peptides that can be used in the conjugates disclosed herein are listed in Table 2. Table 2. Suitable Peptide SequencesPeptide SEQUENCESEQ ID No.CGLFEAIEEFIENLWELLIDGWYGYGRKKRRQRRSEQ ID NO: 1CGLFEAIEGFIENGWEGMIDGWYGYGHKKHHQHHSEQ ID NO: 2C-bAla-LFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 3CGLFEAIEGFIENGLKGLIDWWYGYGRKKRRQRRSEQ ID NO: 4CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 5CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGSEQ ID NO: 6CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRSEQ ID NO: 7CYGRKKRRQRRGLFEAIEGFIENGWEGMIDGWYGSEQ ID NO: 8CIFGAIAGFIKNILKGLIDGSEQ ID NO: 9CIFGAIAGFIRNIWSEQ ID NO: 10CGLFHALLHLLHSLWHGLLHAWYGYGHKKHHQHRSEQ ID NO: 11CGLFEAIEGLIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 12CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 13CGLFEAIEGFIENGWEGLIDGWYGYGOOOOOQRR (O = ornithine)SEQ ID NO: 14CGLFGAIEGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 15CGLFEAIEGFLENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 16CGLFEAIEGFIENGLEGMIDGWYGYGRKKRRQRRSEQ ID NO: 17CGLFGAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 18CGLFEAIEGFIENGWEG-Nle-IDGWYGYGRKKRRQRRSEQ ID NO: 19CGIFGAIAGFIKNIWKGLIDWSEQ ID NO: 20CYGRKKRRQRRGLFEAIEGFIENGWKGLIDAWYGSEQ ID NO: 21CGLLEALEGLLESLWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 22CGLFEAIEGFIENGWEGMIDNWYGYGRKKRRQRRSEQ ID NO: 23CIFGAIAGFIKNIWEGLIEAWYGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 24CIFGAIAGFIKNIWEGLIDAFSEQ ID NO: 25CIFGAIAGFIKNIWEGLISEQ ID NO: 26CGLFEAIEGFIENGWEGMIOGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 27SEQ ID NO: 28SEQ ID NO: 29CGLFEAIEGFIENGWEGMIDGWYGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 30CGLFEALLELLESLWELLLEAYGRKKRRQRRSEQ ID NO: 31CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 32CGLFEAIEGFIENGWEGMADGWYGYGRKKRRQRRSEQ ID NO: 33CGIFGAIAGFIKNIWEGLIDWWYGYGRKKRRQRRSEQ ID NO: 34CGFLPAIAGILSQLFEGLIDGWYGYGRKKRRQRRSEQ ID NO: 35CFFGAIWGFIKSILSEQ ID NO: 36CIFGAIAGFIKNIWKGLIDWWYGSEQ ID NO: 37CGLFEAIEGFIWNGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 38CGLFEAIAEFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 39CYGRKKRRQRRGLFEAIEGFIENGWKGLIDWWYGSEQ ID NO: 40CGLFEAIEGFIEEGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 41CGLFEAIEGFIENAWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 42CGLFEAIEGFIENGWEGMIDLWYGYGRKKRRQRRSEQ ID NO: 43CRLLRLLLRLWRRLLRLLRSEQ ID NO: 44CGGFEAIEGFIENGWEGMIOGWYGYGRKKRRQRRSEQ ID NO: 45CGLFEKIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 46CGLFEAIEGFIENGWENMIDGWYGYGRKKRRQRRSEQ ID NO: 47CIFGAIAGFIKNILKGLSEQ ID NO: 48CIFGAIAGFIKNILKGLIDGWYGSEQ ID NO: 49CGLFEAIEGFIENGWEGMIDGWYG-(PEG)3-YGRKKRRQRRSEQ ID NO: 50SEQ ID NO: 51CYGRKKRRQRRWEAALAEALAEALAEHLAEALAEALEALAASEQ ID NO: 52CIFGAIAGFIKNIWEGLIDGWYGKLALKLALKALKAALKLASEQ ID NO: 53CFFGAIWEFIRSILEGLIDGWYGYGRKKRRQRRSEQ ID NO: 54CGLFHALLHLLHSLWHLLLHAWYGYGRKKRRQRRSEQ ID NO: 55CGLFHALLHLLHSLWHLLLHAWYGYGHKKHHQHRSEQ ID NO: 56CGLFGALLELLESLWKGLLEWYGRKKRRQRRSEQ ID NO: 57CRRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLGSEQ ID NO: 58CGLFEALEGFLENGWEGLLDGWYGYGROORRQRR (O = ornithine)SEQ ID NO: 59CGLFGEIEELIENGLKNLIDWWYGYGRKKRRQRRSEQ ID NO: 60CRRQRRKKRGYGYWWOILGKWGNEIFGEIAEFLG all (D) aminosSEQ ID NO: 61CGIFGAIAGFIKNILSEQ ID NO: 62CGIFGAIAGLLKNIFKSEQ ID NO: 63CIFGAIAGFIKNIWKGLIDWSEQ ID NO: 64CIFGAIAGFIKNIWKSEQ ID NO: 65CGLFEEIEGFIENGWEGLIDWWYGYGHKKHHQHRSEQ ID NO: 66CGLFGEIEELIENGLKNLIDWWYGYGHKKHHQHRSEQ ID NO: 67CGLFEEIEEFIENGWEGLIDWWYGYGHKKHHQHRSEQ ID NO: 68stearyl-WEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRCSEQ ID NO: 69CGLFEAIEGFIENGWKGLIDGWYGGLFEAIEGFIENGWKGLIDWWYGSEQ ID NO: 70CGFFHAFFHFFHSFWHGFFEASEQ ID NO: 71CGNFGEIEELIEEGLENLIDWWNGSEQ ID NO: 72CFFGAIWEFIRNILEGFSEQ ID NO: 73CFFGAIWEFIHSILSEQ ID NO: 74CGLFHALLHLLHSLWHGLLEASEQ ID NO: 75CIFGAIAGFIKNIWEGLSEQ ID NO: 76CIFGAIAGLLKNIFEGLIDGWYGYGRKKRRQRRSEQ ID NO: 77CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRRSEQ ID NO: 78CGLFEAIEELIENLWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 79CGIFGAIAGLLKNIFKGLIDASEQ ID NO: 80CGIFGAIAGLLKNIFKGLIDWSEQ ID NO: 81CGIFEAIAGLLKNIFKSEQ ID NO: 82CGIFEEIAGLLKNIFKSEQ ID NO: 83SEQ ID NO: 84CGLFEAIEGFIENGWKGMIDWWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 85CGLFGEIEEFIENGWKGLIDWWYGSEQ ID NO: 86CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 87CGIFGAIEGFIENGWKGLIDAWYGYRKKRRQRRSEQ ID NO: 88CELFGAIEGFIENGWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 89CIFGIDDLIIGLLFVAIVEAGIGGYLLGSYGRKKRRQRRSEQ ID NO: 90GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 91CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRR all (D)SEQ ID NO: 92CFFGAIWEFIRSILKGLISEQ ID NO: 93CFFGAIWEFIRSILKSEQ ID NO: 94CFFGAIWEFIRSILESEQ ID NO: 95CIFGAIAGFIKNIWESEQ ID NO: 96CIFGAIAGFIKNIWKGLIDASEQ ID NO: 97CFFEAIEEFIKNILKSEQ ID NO: 98CIFGAIAGLLRNIFSEQ ID NO: 99CGIFGAIAGLLKNIWSEQ ID NO: 100CLFGAIWEFIKSILSEQ ID NO: 101CFWGAIWEFIKSILSEQ ID NO: 102CFGGAIWEFIKSILSEQ ID NO: 103CFAGAIWEFIKSILSEQ ID NO: 104CGLFEAIEGFIENGWEGM(SO2)IDGWYGYGRKKRRQRRSEQ ID NO: 105CGLFEAIEGFIENGWEGMIDWWYGYGRKKRRQRRSEQ ID NO: 106CFFGAIWEFIKSIGSEQ ID NO: 107CFFGAIWEFIKSIASEQ ID NO: 108CFFGAIWEFIKSINSEQ ID NO: 109CFFGAIWEFIKSIWSEQ ID NO: 110CFFGAIWEFIKSILEGLIDWWYGYGHKKHHQHRSEQ ID NO: 111Ac-CLHLLHHLLHHLHHLLHHLLHLLHHLLHHLSEQ ID NO: 112Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRKKRRQRRRPPQCSEQ ID NO: 113CRKKRRQRRRPPQGGGLHLLHHLLHHLHHLLHHLLHLLHHLLHHLSEQ ID NO: 114CLHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRKKRRQRRRPPQSEQ ID NO: 115CGLFHAIAHFIHGGWHGLIHGWYGYGRKKRRQRRSEQ ID NO: 116CGLFKAIAKFIKGGWKGLIKGWYGYGRKKRRQRRSEQ ID NO: 117CGLFEAIAGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 118CWEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRSEQ ID NO: 119CGLFEAIEGFIENGWEGMIDGWYGRKKRRQRRRPPQSEQ ID NO: 120GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRCSEQ ID NO: 121Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLRKKRRQRRRPPQSEQ ID NO: 122Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGPGRKKRRQRRRPPQSEQ ID NO: 123Ac-LIRLWSHLIHIWFQNRRLKWKKKSEQ ID NO: 124Ac-RKKRRQRRRPPQQQQQQSEQ ID NO: 125Ac-GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 126Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLGGGRRRRRRRRRSEQ ID NO: 127Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-(Peg)12-RKKRRQRRRPPQSEQ ID NO: 128Ac-GLFGAIAGFIENGWEGMIDGWYGLIRLWSHLIWFQNRRLKWLLLSEQ ID NO: 129SEQ ID NO: 130Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-(Peg)2-RKKRRQRRRPPQSEQ ID NO: 131SEQ ID NO: 132Ac-KLLKLLLKLWLKLLKLLLKLLGGGRKKRRQRRRPPQSEQ ID NO: 133Ac-LHHLLHHLLHLLHHLLHHLHHLLHHLLHLC all (D)SEQ ID NO: 134Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHL-(PEG)6-RKKRRQRRRPPQCSEQ ID NO: 135Ac-GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRCSEQ ID NO: 136CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D)SEQ ID NO: 137CGLFEAIEGFIENGWEGMIDGWYGYGRRRRRRRRRSEQ ID NO: 138YGRKKRRQRRGLFEAIEGFIENGWEGMIDGWYGCSEQ ID NO: 139CGVFVLGFLGFLATAGSYGRKKRRQRRSEQ ID NO: 140CGLFKAIAKFIKGGWKGLIKGWYGSEQ ID NO: 141CGLFEAIEGFIENGWEGMIDGWYGYGRKKRSEQ ID NO: 142CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRYGRKKRRQRRSEQ ID NO: 143CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRYGRKKRRQRRSEQ ID NO: 144CGLFEAIKGFIENGWEGMIOGWYGYGRKKRRQRRSEQ ID NO: 145CGLFEAIHGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 146CGLFEAIRGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 147CGLFEAIDGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 148CRLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 149CGGGLFEAIEGFIENGWEGMIOGWYGYGRKKRRQRRSEQ ID NO: 150CGLFEAIEGFIENGWEGMIOGWYGGGGYGRKKRRQRRSEQ ID NO: 151CGLFEAIEGFIENGWEGMIDGWYG-(PEG)11-YGRKKRRQRRSEQ ID NO: 152CFLGFLLGVGSAIASGIAVSKVLHLSEQ ID NO: 153CGVFVLGFLGFLATAGSAMGARSLTLSAYGRKKRRQRRSEQ ID NO: 154Ac-GLWRALWRLLRSLWRLLWRA-mercaptoethylamideSEQ ID NO: 155C-Nle-LFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 156CELFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 157CGFFGAIAGFLEGGWEGMIAGWHGYGRKKRRQRRSEQ ID NO: 158CFLGFLLGVGSAIASGIAVSKVLHLYGRKKRRQRRSEQ ID NO: 159GLFEAIEGFIENGWEGLAEALAEALEALAAGGSCSEQ ID NO: 160SEQ ID NO: 161SEQ ID NO: 162CGLFGAIAGFIEGGWTGMIDGWYGYGRKKRRQRRSEQ ID NO: 163CGLFGAIAGFIEGGWQGMVDGWYGYGRKKRRQRRSEQ ID NO: 164CGLFGAIAGFIENGWQGLIDGWYGYGRKKRRQRRSEQ ID NO: 165CGLFGAIAGFIENGWEGLVDGWYGYGRKKRRQRRSEQ ID NO: 166CGLFGAIAGFIEGGWSGMIDGWYGYGRKKRRQRRSEQ ID NO: 167CGLFGAIAGFIEGGWPGLVAGWYGYGRKKRRQRRSEQ ID NO: 168CGLFGAIAGFIENGWEGMVDGWYGYGRKKRRQRRSEQ ID NO: 169CGLFGAIAGFIEGGWPGLINGWYGYGRKKRRQRRSEQ ID NO: 170CGLFGAIAGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 171CGLFGAIAGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 172CGLFGAIAGFIENGWEGMIDGWYGSSKKKKSEQ ID NO: 173CGLFGAIAGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 174CGLFEAIEGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 175CGLFGAIAGFIENGWEGLIEGWYGGGRKKRRQRRSEQ ID NO: 176CGLFEAIEGFIENGWEGMIDGWYGGGRKKRRQRRSEQ ID NO: 177CGLFEAIAGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 178CGLFEAIAEFIENGWEGLIEGWYGGRKKRRQRRSEQ ID NO: 179CGLFEAIEGFIENGWEGMIDGWYGRKKRRQRRRSEQ ID NO: 180CKLLKLLLKLWLKLLKLLLKLLSEQ ID NO: 181CKLLKLLLKLWLKLLKLLLKLLYGRKKRRQRRSEQ ID NO: 182GLFEAIEGFIENGWEGMIDGWYGCSEQ ID NO: 183CVLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 184CSLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 185CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQSEQ ID NO: 186CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRSEQ ID NO: 187CGLFEAIEGFIENGWEGMIDGWYGYGKKKKKQKKSEQ ID NO: 188CGLFEAIEGFIENGWEGMIDGWYGGLFEAIEGFIENGWEGMIDGWYGSEQ ID NO: 189SEQ ID NO: 190RRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGCSEQ ID NO: 191CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGSEQ ID NO: 192GLFEAIEGFIENGWEGMIDGWYGYGRK-K(D)-RRQRRSEQ ID NO: 193GLFEAIEGFIENGWEGMIDGWYGYGRKK-R(D)-RQRRSEQ ID NO: 194GL-F(D)-EAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 195GLF-E(D)-AIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 196CGLFEAIEGFIENGWEGMIDGWYGSEQ ID NO: 197CYGRKKRRQRRSEQ ID NO: 198YGRKKRRQRRCSEQ ID NO: 199RRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLGC all(D)SEQ ID NO: 200CRRQRRKKRGYGYWGDIMGEWGNEIFGEIAEFLG all(D)SEQ ID NO: 201CGLFEAIEGFIENGWEGMIDGAYGYGRKKRRQRRSEQ ID NO: 202CGLFEALLELLESLWELLLEAWYGYGRKKRRQRRSEQ ID NO: 203CGLFEAIEGFNENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 204CGLFEAIEGFIENEWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 205K(stearyl)GLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRCSEQ ID NO: 206CGLFEAIK(stearyl)GFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 207CGLFEAIKGFIENGWEGMIDGWYGYGRK(stearoyl)KRRQRRSEQ ID NO: 208CGLFEAIEGFIENPWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 209(stearyl)GLFEAIEGFIENPWEGMIDGWYGYGRKKRRQRRCSEQ ID NO: 210SEQ ID NO: 211SEQ ID NO: 212CGLFEAIAGFIEGGWPGLINGWYGYGRKKRRQRRSEQ ID NO: 213CGLEEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 214CGLFNAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 215CGLFAAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 216CGLFEAIENFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 217CGLFEAIEKFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 218CGLFEAIEGFAENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 219CGLFEAIEGFIENWWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 220CGLFEAIEGFIENNWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 221CGLFEAIEGFIENGEEGMIDGWYGYGRKKRRQRRSEQ ID NO: 222CGLFEAIEGFIENGWAGMIDGWYGYGRKKRRQRRSEQ ID NO: 223CGLFEAIEGFIENGWNGMIDGWYGYGRKKRRQRRSEQ ID NO: 224CGLFEAIEGFIENGWGGMIDGWYGYGRKKRRQRRSEQ ID NO: 225CGLFEAIEGFIENGWEGMIDAWYGYGRKKRRQRRSEQ ID NO: 226CGLFEAIEGFIENGWLGMIDGWYGYGRKKRRQRRSEQ ID NO: 227CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRRSEQ ID NO: 228CGLFEAIEGFIENGWEGMIDKWYGYGRKKRRQRRSEQ ID NO: 229CGLFEAIEGFIENGWEGMIDEWYGYGRKKRRQRRSEQ ID NO: 230CGLFEAIEGFIENGWEGMIDGLYGYGRKKRRQRRSEQ ID NO: 231CGLFEAIEGFIENGWEGMIDGNYGYGRKKRRQRRSEQ ID NO: 232CGLFEAIEGFIENGWEGMIDGKYGYGRKKRRQRRSEQ ID NO: 233CGLFEAIEGFIENGWEGMIDGEYGYGRKKRRQRRSEQ ID NO: 234CGLFEALEELLEGGWEGLIEAWYGYGRKKRRQRRSEQ ID NO: 235CELFGAIWEFIEGGWEGLIEAWYGYGRKKRRQRRSEQ ID NO: 236CGLFEALEEFIEGGWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 237CGLFEALEEFIENGWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 238CGLFEAIEGFIESGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 239CGLFEAIEEFIEGGWEGLIEAWYGYGRKKRRQRRSEQ ID NO: 240CGLFEAIEGFIENGWEGLIDAWYGYGRKKRRQRRSEQ ID NO: 241CGLFEAIEGFILNGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 242CGLFEAIEGFIKNGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 243CGLFEAIEGFIGNGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 244CGLFEAIEGFIELGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 245CGLFEAIEGFIEKGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 246CGLFEAIAEFIEGGWEGLIEGWYGYGRKKRRQRRSEQ ID NO: 247CRGWEVLKYVMINLLQYSEQ ID NO: 248CRGWEVLKYWWNLLQYYGRKKRRQRRSEQ ID NO: 249CGLFGAIAGFIENGWEGMIDGWYGFRYGRKKRRQRRSEQ ID NO: 250Ac-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR-CO2HSEQ ID NO: 251CGLLEALEGLLENGWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 252CLRHLLRHLLRHLRHLLRHLRHLLRHLLRHSEQ ID NO: 253CGIFEAIEGFIENGWEGIIDGWYGYGROORRQRR (O = ornithine)SEQ ID NO: 254CGIGAVLKVLTTGLPALISWIKRKRQQSEQ ID NO: 255CGIGAVLKVLTTGLPALISWIHHHHQQSEQ ID NO: 256CGAFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 257Ac-LHLLHHLLHHLHHLLHHLLHLLHHLLHHLRRRRRSEQ ID NO: 258CGLFGAIWGFIENWWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 259CGLFGAIEGFIENGWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 260CGLFEAIAGFIENGWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 261GLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRRCSEQ ID NO: 262YGRKKRRQRRGLFEAIEGFIENGWKGLIDAWYGCSEQ ID NO: 263YGRKKRRQRRGLFEAIEGFIENGWKGLIDWWYGCSEQ ID NO: 264CGLFHAIHGFIENGWHGLIDWWYGYGRKKRRQRRSEQ ID NO: 265CGLFEAIEGFIENGWKGLIOWWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 266CGLFKALLKLLKSLWKLLLKAWYGYGHKKHHQHRSEQ ID NO: 267CGLFKALLKLLKSLWKGLLKAWYGYGHKKHHQHRSEQ ID NO: 268CGLAKALLKLLKSLWKGLIEAWYGYGRKKRRQRRSEQ ID NO: 269CGIFGAIAGFIKNIWSEQ ID NO: 270CIFGAIAGFIKNIWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 271CGIFGAIAGFIKNIWEGLIDGYGRKKRRQRRSEQ ID NO: 272CGIFGAIAGFIKNIWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 273CIFGAIAGFIKNIWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 274CLFGAIAGFIKNIWSEQ ID NO: 275CGL(R5)EAIEGF(S8)ENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 276CGLFEA(S5)EGF(S5)ENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 277CGLFEAIEGFIENGWEGAIDGWYGYGRKKRRQRRSEQ ID NO: 278CGLFEAIEGFIENGWEGEIDGWYGYGRKKRRQRRSEQ ID NO: 279CGIFGAIAGFIKNGWEGMVDWYGYGRKKRRQRRSEQ ID NO: 280CGLFEAIAGFIENGWEGMIDGWYGFYGRKKRRQRRSEQ ID NO: 281CGIFGAIAGFIKNGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 282CIFGAIAGFIKNIWSEQ ID NO: 283CIFGAIAGFIKNIWYGRKKRRQRRSEQ ID NO: 284CGIFGAIAGFIKNIWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 285CGLFEAIEGFIENGWEGLIEAYGRKKRRQRRSEQ ID NO: 286CGLFEALLGFIENGWEGLIDGYGRKKRRQRRSEQ ID NO: 287CGLFGAIEGFIENGWEGLIDGWYGYGRKKRRQRRRSEQ ID NO: 288CELFGAIEGFIENGWEGMIDGWYGYGRKKRRQRRRSEQ ID NO: 289CGLFEAIEGFIENGWEGMIDGWYGYGHKKHHQHRSEQ ID NO: 290CGLFGAIEGFIEGGWPGLINGWYGYGRKKRRQRRRSEQ ID NO: 291CGLFKALLKLLKSLWKLLLKAYGRKKRRQRRSEQ ID NO: 292CGLFKALLKLLKSLWKLLLKAWYGYGRKKRRQRRSEQ ID NO: 293CGLFRALLRLLRSLWRLLLRAYGRKKRRQRRSEQ ID NO: 294CGLFEAILGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 295CGLFEAIWEFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 296CGLFEAIEGFIENGWEGMIDGWYGGGGLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 297CGPVEDAITAAIGRVADTVGTYGRKKRRQRRSEQ ID NO: 298CMDGTLFPGDDDLAIPATEFFSTKASEQ ID NO: 299CGLFEALEEFIEGGWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 300CGLFEALEEFIENGWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 301CELFGAIWEFIEGGWEGLIEAYGRKKRRQRRSEQ ID NO: 302CGLFEAIEGFIEEGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 303CGLFEAIAEFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 304CGLFEAIAEFIEGLWEGLIEGWYGYGRKKRRQRRSEQ ID NO: 305CGLLEALEGLLESLWEGLLEAWYGYGRKKRRQRRSEQ ID NO: 306CGLFEAIEGFIENGWEGMIDIWYGYGRKKRRQRRSEQ ID NO: 307CGLFEAIEGFIENGWRGMIDGWYGYGRKKRRQRRSEQ ID NO: 308CGLFEAIEGFIENGWDGMIDGWYGYGRKKRRQRRSEQ ID NO: 309CGLFEAIEGFIENHWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 310CGLFEAIEGFIENWWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 311GLFEAIEGFIENGWKGLIDAWYGYGRKKRRQRRCSEQ ID NO: 312CGLFEAIEGFIENGWKGMIDAWYGYGRKKRRQRRSEQ ID NO: 313CGLFEAIEGFIENGWKGMIDWWYGYGRKKRRQRRSEQ ID NO: 314CGLAEAIEGFIENGLKGLIDWWYGYGRKKRRQRRSEQ ID NO: 315RRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLGC all(D)SEQ ID NO: 316CRRQRRKKRGYGYWGDILGEWGNEIFGEIAEFLG all(D)SEQ ID NO: 317CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 318CGFFEAIEGFIENGLKGLIDAWYGYGRKKRRQRRSEQ ID NO: 319CGLFEAIEGFIENGLKGLIDAWYGYGRKKRRQRRSEQ ID NO: 320CELFGAIEGFIENGWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 321CGLFKAIKGFIKNGWKGLIKAWYGYGRKKRRQRRSEQ ID NO: 322CGLAEALLELLESLWKGLIEAYGRKKRRQRRSEQ ID NO: 323CGIFGAIEGFIENGWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 324CGIAGAIAGFIKNIWEGLIDWWYGYGRKKRRQRRSEQ ID NO: 325CGIAGAIAGFIKNIWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 326CGIFGAIAGFIKNIWEGLIDGWYGKKKKKKKKKSEQ ID NO: 327CG(R5)FEAIEG(S8)IENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 328CGLFEAIEGF(R5)ENGWEG(S8)IDGWYGYGRKKRRQRRSEQ ID NO: 329GLFEAIEGFIENGWEGMIDGWYGCYGRKKRRQRRSEQ ID NO: 330GLFEAIEGFIENGWEGMIDGWYGGCGYGRKKRRQRRSEQ ID NO: 331GLLEALEGLLENGWEGLLDGWYGYGRKKRRQRRSEQ ID NO: 332CFFGAIWEFIRNILSEQ ID NO: 333CIFGAIAGFIRSILSEQ ID NO: 334CGLFEEIEEFIENGWEGLIDWWYGYGRKKRRQRRSEQ ID NO: 335CGFFGAIWEFIKSILSEQ ID NO: 336GFFGAIWEFIKSILCSEQ ID NO: 337CGLFEALEGFIENGWEGLLDGWYGYGROORRQRR (O = ornithine)SEQ ID NO: 338CGLFEALLELLENGWELLLEAWYGYGRKKRRQRRSEQ ID NO: 339CGLFEALLELLENGWELLLDGWYGYGRKKRRQRRSEQ ID NO: 340CALFEAIEAFIENGWEAMIDAWYGYGRKKRRQRRSEQ ID NO: 341CGLFGAIWGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 342CGLFEAIEELIENLWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 343CGLFEEIEGFIENGWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 344CGLFEEIEGFIENGWKGLIDWWYGYGHKKHHQHRSEQ ID NO: 345CFFGAIWEFIKNILKGLIDGWYGSEQ ID NO: 346CGIFGAIAGFIRSILSEQ ID NO: 347CGLFEEIEGFIENGWEGMIOGWYGYGRKKRRQRRSEQ ID NO: 348CGLFEAIEGFIENGWEGMIDGWNGYGRKKRRQRRSEQ ID NO: 349AGYLLGKINLKALAALAKKILHHHHHHKKKKKKCSEQ ID NO: 350Bis CGLFEAIEGFIENGWEGMIDWWYGYGRKKRRQRRSEQ ID NO: 351CGLFEAIEGFIENGWEGMIDGWYG-(PEG)6-YGRKKRRQRRSEQ ID NO: 352CGIFGAIWNGIKSLFEGLIDGWYGYGRKKRRQRRSEQ ID NO: 353CGIFGAIEGFIENGWEGLIDWWYGYGRKKRRQRRSEQ ID NO: 354CIFGAIAGFIKNIWEGLIDWWYGYGRKKRRQRRSEQ ID NO: 355CGLFEAIEGFIENGWKGLIDGWYGGLFEAIEGFIENGWKGLIDWWYGSEQ ID NO: 356CWEAALAEALAEALAEHLAEALAEALEALAAYGRKKRRQRRK(stearyl)SEQ ID NO: 357CGLFEAIEGFIENGWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 358CGLFEELEELLEEGWEGLLEAYGRKKRRQRRSEQ ID NO: 359CGNFEEIEEFIEEGLRNFIDWWYGYGHKKHHQHRSEQ ID NO: 360CFFGAIWEFIRNILEGLIDWWYGYGRKKRRQRRSEQ ID NO: 361CFFGAIWEFIKNILLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 362CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRR all(D)SEQ ID NO: 363CGFFHAFFHFFHSFWHGFFEASEQ ID NO: 364CGLFHALLHLLHSLWHGLLHWWYGYGHKKHHQHRSEQ ID NO: 365CGLFGALLELLESLWEGLLEWYGRKKRRQRRSEQ ID NO: 366CGLFGALLELLESLWEGLLEWYGH KKHHQHRSEQ ID NO: 367CGLFHALLHLLHSLWKGLLEWWYGFSEQ ID NO: 368CIFGAIAGFIRSILEGFSEQ ID NO: 369CGIFGAIAGFIKNIWKGLIDASEQ ID NO: 370CFFEAIEEFIKNIWKSEQ ID NO: 371CGLFEAIEGFIENGWKGLIDWLAEALAEALEALAASEQ ID NO: 372GCGIFGAIAEFIKNIWSEQ ID NO: 373CIFGAIAEFIKNIWKGLIDWSEQ ID NO: 374CFFGAIWEFIKSILELLLEAYGHKKHHQHRRSEQ ID NO: 375CWFGAIWEFIKSILSEQ ID NO: 376CAFGAIWEFIKSILSEQ ID NO: 377CFLGAIWEFIKSILSEQ ID NO: 378CFFGAIWEFIKSIKSEQ ID NO: 379CGFIGAIANLLSKIFEGLIDGWYGYGRKKRRQRR all(D)SEQ ID NO: 380CFFGAIWEFIKSILSEQ ID NO: 381CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHL all(D)SEQ ID NO: 382CFFGAIAEFIKNIWSEQ ID NO: 383CIFEAIWGFIKNIWSEQ ID NO: 384(stearyl)-AGYLLGKINLKALAALAKKILHHHHHHKKKKKKCSEQ ID NO: 385CIFEAIAGFIKNIWKGLIDWWYGYGRKKRRQRRSEQ ID NO: 386CGLFEAIEGFIENGWKGLIDWWYGGRPRESGKKRKRKRLKPSEQ ID NO: 387C(b-Ala)GFGEIEEFIENGLKNLIOWWYGYGHKKHHQHRSEQ ID NO: 388C(b-Ala)GFEFIEEFIENGLKNLIDWWYGYGRKKRRQRRSEQ ID NO: 389C(b-Ala)GFEFIEEFIENGLKNLIDWWYGYGHKKHHQHRSEQ ID NO: 390CGGIEEIAGLLSKILKGLIDWWYGYGHKKHHQHRSEQ ID NO: 391CGFIGAIANLLSKIFEGLIDWWYGYGRKKRRQRRSEQ ID NO: 392CGFIGAIAELLEKIFEGLIDWWYGYGRKKRRQRRSEQ ID NO: 393CGFIGAIAELLEKIFEGLIDWWYGYGHKKHHQHRSEQ ID NO: 394CFFGAIWEFIRNILEGLIDWWYGYGHKKHHQHRSEQ ID NO: 395CFFGAIWEFIKSILLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 396CFFGAIWEFIRSILLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 397CGFFGAIWEFIRSILEGFIDWWYGYGYGHKKHHQHRSEQ ID NO: 398CGLFEAIWEFIKSILEGLLEAYGHKKHHQHRSEQ ID NO: 399CGLFEAIWEFIKSILEGLLEAWYGYGHKKHHQHRSEQ ID NO: 400CGIFGAIAGFIKNIWKYGRKKRRQRRSEQ ID NO: 401CGLFEALLELLESLWELLLEAWYGYGHKKHHQHRSEQ ID NO: 402CIFGAIAGFIRNIWKGLIDGWYGSEQ ID NO: 403CGIFGAIAGFIRNIWKGLIDGWYGSEQ ID NO: 404CFFGAIWEFIKNILKLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 405CFFGAIWEFIRNILLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 406CFFGKIWEFIKSILSEQ ID NO: 407CYGRKKRRQRRGLFEALLELLESLWELLLEASEQ ID NO: 408FFGAIWEFIKSILCSEQ ID NO: 409CWWGAIEGFIKSILSEQ ID NO: 410CFFGAIWEWIKSILSEQ ID NO: 411CFFGAIWEFWKSILSEQ ID NO: 412CFFGAIWEFIKFILSEQ ID NO: 413CFFGAIWEFIKKILSEQ ID NO: 414CFFGAIWEFIKGILSEQ ID NO: 415CFFGAIWEFIKLILSEQ ID NO: 416CFFGAIWEFIKWILSEQ ID NO: 417CFFGAIWEFIKSFLSEQ ID NO: 418CFFGAIWEFIKSKLSEQ ID NO: 419CFFGFIWEFIKSILSEQ ID NO: 420CIFGAIAGFIKNILKGLIDAFSEQ ID NO: 421CFFGKIWELWEWILSEQ ID NO: 422CFFGAIWEFAKSILSEQ ID NO: 423CFFGAIWEFIKSALSEQ ID NO: 424CFFGAIWEFIKSWLSEQ ID NO: 425CFFGAIWEFIKSILKSEQ ID NO: 426CFFGAIWEFIKSILESEQ ID NO: 427CFFKAIWEFIKSILSEQ ID NO: 428CFFNAIWEFIKSILSEQ ID NO: 429CFFGGIWEFIKSILSEQ ID NO: 430CFFGNIWEFIKSILSEQ ID NO: 431CFFGALWEFIKSILSEQ ID NO: 432CFFGAAWEFIKSILSEQ ID NO: 433CGLFHALLHLLHSLWHGLLDGSEQ ID NO: 434CGLFHALLHLLHSLWHGLLEWSEQ ID NO: 435CGLFHALLHLLHSLWHLLLEASEQ ID NO: 436CGLFHALLHLLHSLWKLLLEWSEQ ID NO: 437CKFGAIWEFIKSILSEQ ID NO: 438CFKGAIWEFIKSILSEQ ID NO: 439CFFGAIWKFIKSILSEQ ID NO: 440CFFGAIWAFIKSILSEQ ID NO: 441CFFGAIWLFIKSILSEQ ID NO: 442CFFGAIWFFIKSILSEQ ID NO: 443CFFGAIWNFIKSILSEQ ID NO: 444CFFGAIWELIKSILSEQ ID NO: 445CFFGAIWEAIKSILSEQ ID NO: 446CGLFEAIEGFIENGWEGLAEALAEALEALAAYGRKKRRQRRSEQ ID NO: 447CIFGAIAGFIKNIWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 448CIFGAIAGFIKNIWEGLIDAWYGYGRKKRRQRRSEQ ID NO: 449CIFGAIAGFIKNIWKGLIDAWYGYGRKKRRQRRSEQ ID NO: 450CIFGAIAGFIKNIWIFGAIAGFIKNIWWYGYGRKKRRQRRSEQ ID NO: 451CGLFGAIAGFIENGWEGLIEGWYGSEQ ID NO: 452CGLFEAIEGFIENGWEGLIDGWYGYGOOOOOQRR (O = ornithine)SEQ ID NO: 453CGLFEAIEGFIENGVWGLIDWONGYGRKKRRQRRSEQ ID NO: 454CGLFEAIEGFIENGWEGLIOGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 455CYGHKKHHQHRGLFEAIEGFIENGWKGLIDWWYGSEQ ID NO: 456CYGHKKHHQHRGLFEAIEEFIENGWEGLIDGWYGSEQ ID NO: 457CGLFEAIEGFIENGWKGLIDGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 458CGLFEAIEGFIENGWHGMIDGWYGYGRKKRRQRRSEQ ID NO: 459IFGIDDLIIGLLFVAIVEAGIGGYLLGSYGRKKRRQRRCSEQ ID NO: 460CGFFGEIAELIEEGLKGLIDWWNGSEQ ID NO: 461CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 462CFFGAIWEFIHSIL all (D)SEQ ID NO: 463CFFGAIWEFIHNILSEQ ID NO: 464CFFGAIWEFIHSIFKSEQ ID NO: 465CGIFEAIAGLLKWIFKSEQ ID NO: 466CGIFELIAGLLKNIFKSEQ ID NO: 467CGIFEAIAGLLKSILKK(stearyl)SEQ ID NO: 468CGIFGAIAGLLKSILKK(stearyl)SEQ ID NO: 469CIFGAIAGFIKNILKGL all (D)SEQ ID NO: 470CIFGAIAGFIKNILKGLIDGWWYGSEQ ID NO: 471CIFGAIAGFIKNIWHGLISEQ ID NO: 472CIFGAIAGFIKNILKGLK(stearyl)SEQ ID NO: 473GLGKLINKIFGAIAGFIC all (D)SEQ ID NO: 474CGIFEAIAGLLKNIFDSEQ ID NO: 475CGIFEAIAGLLKNIFESEQ ID NO: 476CGIFEAIAGLLKNIFRSEQ ID NO: 477CGIFEAIAGLLKNIFHSEQ ID NO: 478CGIFEAIAGLLKNIFO (O = ORNITHINE)SEQ ID NO: 479CGIFEAIAGLLKNIFNSEQ ID NO: 480CGIFEAIAGLLKNIFCit (Cit = citrulline)SEQ ID NO: 481CGIFEAIWGLLKNIFKSEQ ID NO: 482CGIFGAIWGLLKNIFKSEQ ID NO: 483CIFGAIAGLLKNIFKSEQ ID NO: 484CIFEAIAGLLKNIFKSEQ ID NO: 485CFFGAIAGLLKNIFKSEQ ID NO: 486CFFEAIAGLLKNIFKSEQ ID NO: 487CGFFEAIAGLLKNIFKSEQ ID NO: 488CIFGAIAGFIKNIWEGLI all (D)SEQ ID NO: 489CIFGAIAGLLKNIFK all(D)SEQ ID NO: 490CGLFGEIEELIEEGLENLIDWWNG all(D)SEQ ID NO: 491CGNFGEIEELIEEGLENLIDWWNG all(D)SEQ ID NO: 492CGFFGEIAELIEEGLKGLIDWWNG all(D)SEQ ID NO: 493CGLFGEIEELIEEGLENLIDWWNESEQ ID NO: 494CGFFGAIAGLLKNIFKSEQ ID NO: 495CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 496CGLFELIEGFIEWGWEGMIDGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 497SEQ ID NO: 498SEQ ID NO: 499CIFGAIAGFIKNIWEGLIK(2H,2H,3H,3H-perfluorononanoyl)SEQ ID NO: 500CIFGAIAGFIKNIWEGLIK(2H,2H,3H,3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 501SEQ ID NO: 502SEQ ID NO: 503SEQ ID NO: 504SEQ ID NO: 505CFFGAIWEFIHSILK(2H,2H,3H,3H-perfluorononanoyl)SEQ ID NO: 506CFFGAIWEFIHSILK(2H,2H,3H,3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 507CIFGAIAGFIKNILKGLK(2H,2H,3H,3H-perfluorononanoyl)SEQ ID NO: 508CIFGAIAGFIKNILKGLK(2H,2H,3H,3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 509CFFGAIWEFIRNILEGFK(2H,2H,3H,3H-perfluorononanoyl)SEQ ID NO: 510CFFGAIWEFIRNILEGFK(2H,2H,3H,3H-perfluoro-10 methylundecanoyl)SEQ ID NO: 511CGLFGEIEELIEEGLENLIDWWNQSEQ ID NO: 512CGIFGAIAGLLKSALKSEQ ID NO: 513CGIFEAIAGLLKSIWKSEQ ID NO: 514CGIFEAIAGLLKSILKSEQ ID NO: 515CGIFEAIAGLLONIFK (O = Ornithine)SEQ ID NO: 516CGIFEAIAGLLKNILKGLIDGWYGSEQ ID NO: 517CGIFGAIAGLLKNILKGLIDGWYGSEQ ID NO: 518CGIFGAIAGLLKNIFKGLIDGWYGSEQ ID NO: 519CGIFGAIWELWEWILKSEQ ID NO: 520CGIFEAIWELWEWILKSEQ ID NO: 521CGLFEAIEGFIENGWEGMIDGWYGK(stearyl)SEQ ID NO: 522(stearyl)GLFEAIEGFIENGWEGMIDGWYGCSEQ ID NO: 523CFLE-Aib-LWKLLEHLLSEQ ID NO: 524CFLE-Aib-LWELLEHLLSEQ ID NO: 525CFLEALWE-Aib-LEHLLSEQ ID NO: 526CFLE-Aib-LWE-Aib-LEHLLSEQ ID NO: 527CFLE-Aib-LWEALEKLFSEQ ID NO: 528(stearyl)IFGAIAGFIKNIWEGLICSEQ ID NO: 529CIFGAIAGFIKNIWEGLIK(stearyl)SEQ ID NO: 530(stearyl)FFGAIWEFIKSILCSEQ ID NO: 531CFFGAIWEFIKSILK(stearyl)SEQ ID NO: 532(stearyl)FFGAIWEFIHSILCSEQ ID NO: 533CFFGAIWEFIHSILK(stearyl)SEQ ID NO: 534(stearyl)GIFEAIAGLLKNIFKCSEQ ID NO: 535CGIFEAIAGLLKNIFK(stearyl)SEQ ID NO: 536CGIFEAIAGLLKNIFKK(stearyl)SEQ ID NO: 537(stearyl)IFGAIAGFIKNILKGLCSEQ ID NO: 538CIFGAIAGFIKNILKGLK(stearyl)SEQ ID NO: 539CIFGAIAGFIKNILKGLSEQ ID NO: 540CGLFGEIEELIEEGLENLIDWWNSSEQ ID NO: 541CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 542CGFFGEIAELIEEGLKNLIDWWNGSEQ ID NO: 543CGLFEAIEGFIENGWKGMIDGWYGYGRKKRRQRRSEQ ID NO: 544CGLFEAIEGFIEWGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 545CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 546CIFGAIAGFIKNIWEGLISEQ ID NO: 547CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 548CGLFEEIEGFIENGWEGLIDWWYGYGHKKGGQHRSEQ ID NO: 549CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 550CGLFEALLELLESLWELLEAYGRKKRRQRRSEQ ID NO: 551CGLFEALLELLESLWELLEAYGRKKRRQRRSEQ ID NO: 552CFFGAIWEFIRNILEGFSEQ ID NO: 553CFFGAIWEFIRNILEGFK(stearyl)SEQ ID NO: 554CIFGAIAGFIKNIWEGLIK(lauryl)SEQ ID NO: 555(lauryl)FFGAIWEFIKSILCSEQ ID NO: 556CFFGAIWEFIKSILK(lauryl)SEQ ID NO: 557(lauryl)FFGAIWEFIHSILCSEQ ID NO: 558CFFGAIWEFIHSILK(lauryl)SEQ ID NO: 559(lauryl)GIFEAIAGLLKNIFKCSEQ ID NO: 560CGIFEAIAGLLKNIFK(lauryl)SEQ ID NO: 561CFFGAIWEFIRNILEGFK(lauryl)SEQ ID NO: 562(lauryl)GLFEAIEGFIENGWEGMIDGWYGCSEQ ID NO: 563CGLFEAIEGFIENGWEGMIDGWYGK(lauryl)SEQ ID NO: 564CGKFTIVFPHNQKGNWKNVPSNYHYK(stearyl)SEQ ID NO: 565CMDGTLFPGDDDLAIPATEFFSTKAK(stearyl)SEQ ID NO: 566CNPVENYIDEVLNEVLVVPNINSSNK(stearyl)SEQ ID NO: 567CVTPHHVLVDEYTGEWVDSQFK(stearyl)SEQ ID NO: 568CIFGIDDLIIGLLFVAIVEAGIGGYLLGSK(stearyl)SEQ ID NO: 569CGAAIGLAWIPYFGPAAEK(stearyl)SEQ ID NO: 570CFAGVVLAGAALGVATAAQITAGIALHK(stearyl)SEQ ID NO: 571CFLGFLLGVGSAIASGIAVSKVLHLK(stearyl)SEQ ID NO: 572CFFGAVIGTIALGVATSAQITAGIALAK(stearyl)SEQ ID NO: 573CFFGAVIGTIALGVATAAQITAGIALAK(stearyl)SEQ ID NO: 574GLFEAIAGFIENGGWEGMIDGGGK(stearyl)SEQ ID NO: 575GLFKAIAKFIKGGWKGLIKGWYGK(stearyl)SEQ ID NO: 576GLFHAIAHFIHGGWHGLIHGWYGK(stearyl)SEQ ID NO: 577CGLFEAIAEFIENGWEGLIEGWYGK(stearyl)SEQ ID NO: 578CGFFGAIAGFLEGGWEGMIAGWHGK(stearyl)SEQ ID NO: 579CFAGVVIGLAALGVATAAQVTAAVALVKK(stearyl)SEQ ID NO: 580CAVGIVGAMFLGFLGAAGSTMGAVSLTLTVQAK(stearyl)SEQ ID NO: 581CGVFVLGFLGFLATAGSAMGARSLTLSAK(stearyl)SEQ ID NO: 582CVPFVLGFLGFLGAAGTAMGAAATALTVK(stearyl)SEQ ID NO: 583CAVPVAVWLVSALAMGAGVAGGITGSMSLASGK(stearyl)SEQ ID NO: 584CGLASTLTRWAHYNALIRAFK(stearyl)SEQ ID NO: 585CGPVEDAITAAIGRVADTVGTK(stearyl)SEQ ID NO: 586CGLGQMLESMIDNTVREVGGAK(stearyl)SEQ ID NO: 587CGLFEAIEGFIENGWEGMIDGWYGFK(stearyl)SEQ ID NO: 588(D)-(cgl)FEAIEGFIENGWEGMIDGWYGYGRKKRR(D)-(qrr)SEQ ID NO: 589CG(lf)LEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 590CIFGIDDLIIGLLFVAIVEAGIGGYLLGS(stearyl)SEQ ID NO: 591CVTVLALGALAGVGVG(stearyl)SEQ ID NO: 592CLLGRRGWEVLKYWWNLLQYWSQEL(stearyl)SEQ ID NO: 593CGIFEAIAGLLKNIFDSEQ ID NO: 594CGIFEAIAGLLKNIFESEQ ID NO: 595CGIFEAIAGLLKNIFRSEQ ID NO: 596CGIFEAIAGLLKNIFHSEQ ID NO: 597CGIFEAIAGLLKNIFO (O = ORNITHINE)SEQ ID NO: 598CGIFEAIAGLLKNIFNSEQ ID NO: 599CGIFEAIAGLLKNIFCit (Cit = citrulline)SEQ ID NO: 600CGIFGAIWGLLKNIFKSEQ ID NO: 601CIFEAIAGLLKNIFKSEQ ID NO: 602CFFEAIAGLLKNIFKSEQ ID NO: 603CGFFEAIAGLLKNIFKSEQ ID NO: 604CGIFEAIAGLLKNIFKGSEQ ID NO: 605CGIFEAIAGLLKNIFKGLSEQ ID NO: 606CGIFEAIAGLLKNIFKGLISEQ ID NO: 607CGIFEAIAGLLKNIFKGLIDSEQ ID NO: 608CGIFEAIAGLLKNIFKGLIDGSEQ ID NO: 609CGIFEAIAGLLKNIFKGLIDGFSEQ ID NO: 610CGIFEAIAGLLKNIFKGLIDGWYGSEQ ID NO: 611CGIFEAIAGLLKNIFK all(D)SEQ ID NO: 612CGIFEAIAGLLKSILKSEQ ID NO: 613CGIFEAIAGLLKNIFKASEQ ID NO: 614CGIFEAIAGLLKNIFKLSEQ ID NO: 615CGIFEAIAGLLKNIFKWSEQ ID NO: 616CGIFEAIAGLLKNIFKFSEQ ID NO: 617CGIFEAIAGLLKNAFKSEQ ID NO: 618CGIFGAIAGLLKNAFKSEQ ID NO: 619CGIFEAIAGLLONIFO (O = Ornithine)SEQ ID NO: 620CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFKSEQ ID NO: 621CGIFEAIAGLLKNIFKFFGAIWEFIHSILSEQ ID NO: 622CFFGAIWEFIHSILGIFEAIAGLLKNIFKSEQ ID NO: 623CFFGAIWEFIHSILFFGAIWEFIHSILSEQ ID NO: 624CFFGAIWEFIHSILGFFGAIWEFIHSILSEQ ID NO: 625CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFKSEQ ID NO: 626CGIFEAIAGLLKNIFKFFGAIWEFIHSILSEQ ID NO: 627CFFGAIWEFIHSILGIFEAIAGLLKNIFKSEQ ID NO: 628CGLFHALLHLLHSLWHLLLEASEQ ID NO: 629CGLFHALLHLLHSLWHLLLEAK(stearyl)SEQ ID NO: 630CGLFHALLHLLHSLWHLLLEAK(stearyl)SEQ ID NO: 631(stearyl)GLFHALLHLLHSLWHLLLEACSEQ ID NO: 632CFFGNIWEFIKSILSEQ ID NO: 633CFFGAIWLFIKSILSEQ ID NO: 634CFFGAIWNFIKSILSEQ ID NO: 635CFFGAIWGFIKSILSEQ ID NO: 636CFLGALFKALSKLLSEQ ID NO: 637CFLGALFHALSKLLSEQ ID NO: 638CFLGALFKALSHLLSEQ ID NO: 639CFLGALFHALSHLLSEQ ID NO: 640FLGALFKALSKLLCSEQ ID NO: 641FLGALFHALSKLLCSEQ ID NO: 642FLGALFKALSHLLCSEQ ID NO: 643FLGALFHALSHLLCSEQ ID NO: 644CFLGALFKALKSLLSEQ ID NO: 645CFLGALFHALKSLLSEQ ID NO: 646CFLGALFKALHSLLSEQ ID NO: 647CFLGALFHALHSLLSEQ ID NO: 648FLGALFKALKSLLCSEQ ID NO: 649FLGALFHALKSLLCSEQ ID NO: 650FLGALFKALHSLLCSEQ ID NO: 651FLGALFHALHSLLCSEQ ID NO: 652CGIFGAIAGFIKNIWKGLIDWSEQ ID NO: 653CGLFEAIEGFIENGWEG-Nle-IDGWYGYGRKKRRQRRSEQ ID NO: 654CGLFEAIEGFIENGLKGLIDWWYGYGRKKRRQRRSEQ ID NO: 655CGLFEAIEGFIENAWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 656CGLFEAIEGFIENGWEGMIDLWYGYGRKKRRQRRSEQ ID NO: 657CRLLRLLLRLWRRLLRLLRSEQ ID NO: 658CGIFGAIEGFIENGWKGLIDAWYGYRKKRRQRRSEQ ID NO: 659CFFGAIWEFAHGILSEQ ID NO: 660CFFGAIWEFARGILEGFSEQ ID NO: 661FFGAIWEFAHGILCSEQ ID NO: 662FFGAIWEFARGILEGFCSEQ ID NO: 663CFFGAIWEFAHSILSEQ ID NO: 664FFGAIWEFAHSILCSEQ ID NO: 665CFFGAIWEFARSILKSEQ ID NO: 666FFGAIWEFARSILKCSEQ ID NO: 667CGIFEAIAGLAKNIFKSEQ ID NO: 668GIFEAIAGLAKNIFKCSEQ ID NO: 669CGIFEAIAGLAKNIFHSEQ ID NO: 670CGIFEAIAGLAHNIFHSEQ ID NO: 671CGIFEAIAGLAHNIFKSEQ ID NO: 672GIFEAIAGLAKNIFHCSEQ ID NO: 673GIFEAIAGLAHNIFHCSEQ ID NO: 674CFLGALWKALSKLLSEQ ID NO: 675CFLGALWHALSKLLSEQ ID NO: 676CFLGALWKALSHLLSEQ ID NO: 677CFLGALWHALSHLLSEQ ID NO: 678FLGALWKALSKLLCSEQ ID NO: 679FLGALWHALSKLLCSEQ ID NO: 680FLGALWKALSHLLCSEQ ID NO: 681FLGALWHALSHLLCSEQ ID NO: 682CGIFGAIAGLLKNAFKSEQ ID NO: 683CIFEAIAGLLKNAFKSEQ ID NO: 684CIFGAIAGLLKNAFKSEQ ID NO: 685CIFEAIWEFIKNIWSEQ ID NO: 686CIFEAIAEFIKNIWSEQ ID NO: 687CIFGAIWEFIKNIWSEQ ID NO: 688CIFGAIAEFIKNIWSEQ ID NO: 689CGIFGIAIGFKINIWSEQ ID NO: 690CGIFEAIAGLLHNIFKSEQ ID NO: 691CGIFEAIWGLLHNIFKSEQ ID NO: 692CGFFEAIAGLLHNIFKSEQ ID NO: 693CGIFEAIAALLKNIFKSEQ ID NO: 694CGIFEAIEGLLKNIFKSEQ ID NO: 695CGIFEAIAGFFKNIFKSEQ ID NO: 696CGIFEAIAGWWKNIFKSEQ ID NO: 697CGIFEAIAGLLKNIWKSEQ ID NO: 698CGIFEAIAELLKNIFKSEQ ID NO: 699CGIFGAIAGLLKSALKSEQ ID NO: 700CGIFEAIAGLLKSIWKSEQ ID NO: 701CGIFEAIAGLLKSILKSEQ ID NO: 702CGIFEAIAGLLKNIFKGLIDASEQ ID NO: 703CGIFEAIAGLLKNIFKGLIDAFSEQ ID NO: 704CGIFEAIAGLLKNIFKGLIDAWYGSEQ ID NO: 705CGIFEAIAGLLKNIFKGLIDAWYGFSEQ ID NO: 706CGIFEAIAGLLKNIFKGLIDGWYGFSEQ ID NO: 707CGIFEAIAGLLKNIFKGLIDWSEQ ID NO: 708CGIFEAIAGLLKNIFKGLIDWFSEQ ID NO: 709CGIFEAIAGLLKNIFKGLIDWWYGSEQ ID NO: 710CGIFEAIAGLLKNIFKGLIDWWYGFSEQ ID NO: 711CGIFELIAGLLKNIFKSEQ ID NO: 712CGIFEAIAGLLKWIFKSEQ ID NO: 713CGIFELIAGLLKWIFKSEQ ID NO: 714CGIFELIAGLLKNIFKGSEQ ID NO: 715CGIFEAIAGLLKWIFKGSEQ ID NO: 716CGIFELIAGLLKWIFKGSEQ ID NO: 717CGLFEALLGLLESLWKSEQ ID NO: 718CGIFEAIAELLKNIFKSEQ ID NO: 719CGIFEALLGLLKSLWKSEQ ID NO: 720CGIFEALLELLKSLWKSEQ ID NO: 721CGIFEAIAGLLKNIFKSEQ ID NO: 722CEIFEAIAGLLKNIFKSEQ ID NO: 723CEIFGAIAGLLKNIFKSEQ ID NO: 724CGLFEAIAGLLKNLFKSEQ ID NO: 725CGIWEAIAGLLKNIWKSEQ ID NO: 726CGLFGAIAGLLKNLFKSEQ ID NO: 727CGIWGAIAGLLKNIWKSEQ ID NO: 728CGIFDAIAGLLKNIFKSEQ ID NO: 729CGIFDAIWGLLKNIFKSEQ ID NO: 730CGIFGGIGGLLKNIFKSEQ ID NO: 731CAIFAAIAALLKNIFKSEQ ID NO: 732CGIFEAIAGLLKNIFSEQ ID NO: 733CGIFEAIAGLLKNISEQ ID NO: 734CGIFEAIAGLLKNSEQ ID NO: 735CGIFEAIAGLLKSEQ ID NO: 736CVIFEAIAGLLKNIFKSEQ ID NO: 737CSIFEAIAGLLKNIFKSEQ ID NO: 738CGIFEEIAGLLKNIFKSEQ ID NO: 739CGIFEEIWGLLKNIFKSEQ ID NO: 740CGIFEAIEELLKNIFKSEQ ID NO: 741CGIFEAIAGLWKNIFKSEQ ID NO: 742CGIFEAIAGLLENIFKSEQ ID NO: 743CGIFEAIAGLLWNIFKSEQ ID NO: 744CGIFEAIAGLLKEIFKSEQ ID NO: 745CGIFEAIAGLLKNILKSEQ ID NO: 746CGIFEAIAGLLRNIFKSEQ ID NO: 747CGIFEAIAGLLKSIFKSEQ ID NO: 748CGIFEAIAGLLKNILKSEQ ID NO: 749CGFFGAIWEFIKSILKSEQ ID NO: 750CGFFEAIWEFIKSILKSEQ ID NO: 751CGFFGAIWGLLKSILKSEQ ID NO: 752CGFFEAIWGLLKSILKSEQ ID NO: 753CGFFEAIAGLLKSILKSEQ ID NO: 754CGFFGAIAGLLKSILKSEQ ID NO: 755CGIFEAIAGLLKNIFEGLISEQ ID NO: 756CGIFEAIWGLLKNIFKGLISEQ ID NO: 757CGIFEAIWGLLKNIFEGLISEQ ID NO: 758CGIFEAIAGLLKNILKGLIDGWYGSEQ ID NO: 759CGIFGAIAGLLKNILKGLIDGWYGSEQ ID NO: 760CGIFGAIAGLLKNIFKGLIDGWYGSEQ ID NO: 761CGIFGAIWELWEWILKSEQ ID NO: 762CGIFEAIWELWEWILKSEQ ID NO: 763CIFGAIWELWEWILKSEQ ID NO: 764CIFEAIWELWEWILKSEQ ID NO: 765CGIFEAIAELWKNIFKSEQ ID NO: 766CGIFEAIAELWENIFKSEQ ID NO: 767CGIFEAIAELWKWIFKSEQ ID NO: 768CGIFEAIAELWEWIFKSEQ ID NO: 769CGIFEAIAGLLKNILKGLIDWWYGSEQ ID NO: 770CGIFGAIAGLLKNILKGLIDWWYGSEQ ID NO: 771CGIFGAIAGLLKNIFKGLIDWWYGSEQ ID NO: 772CGIFEAIAGLLKNILKGLIDGWYGFSEQ ID NO: 773CGIFGAIAGLLKNILKGLIDGWYGFSEQ ID NO: 774CGIFGAIAGLLKNIFKGLIDGWYGFSEQ ID NO: 775CGIFGAIAELLEKIFESEQ ID NO: 776CGIFEAIAELLEKIFESEQ ID NO: 777CGFIGAIAELLEKIFESEQ ID NO: 778CGIFGAIAELLEKIFKSEQ ID NO: 779CGIFEAIAELLEKIFKSEQ ID NO: 780CGFIGAIAELLEKIFKSEQ ID NO: 781CGLFHALLHLLHSLWHLLLEASEQ ID NO: 782GLFHALLHLLHSLWHGLLEACSEQ ID NO: 783GFFHAFFHFFHSFWHGFFEACSEQ ID NO: 784GLFHALLHLLHSLWHLLLEACSEQ ID NO: 785CGLFHALLHLLHSLWHGLLEAK(stearyl)SEQ ID NO: 786CGFFHAFFHFFHSFWHGFFEAK(stearyl)SEQ ID NO: 787CGLFHALLHLLHSLWHLLLEAK(stearyl)SEQ ID NO: 788(stearyl)GLFHALLHLLHSLWHGLLEACSEQ ID NO: 789(stearyl)GFFHAFFHFFHSFWHGFFEACSEQ ID NO: 790(stearyl)GLFHALLHLLHSLWHLLLEACSEQ ID NO: 791CGFFHAFFHFFHSFWHFFFEASEQ ID NO: 792CGFFHAFFHFFHSFWHLFFEASEQ ID NO: 793CGLFHALLHLLHSLWHGLLEWSEQ ID NO: 794CGLFHALLHLLHSLWHLLLEWSEQ ID NO: 795CGFFHAFFHFFHSFWHGFFEWSEQ ID NO: 796CFFGAIWEFAKSILSEQ ID NO: 797CFFGAIWEFAHSILSEQ ID NO: 798CFFGAIWEFAHGILSEQ ID NO: 799CFFGAIWEFIHSILKSEQ ID NO: 800CFFGAIWEFIHSILHSEQ ID NO: 801CFFGAIWEFIHSILDSEQ ID NO: 802CFFGAIWEFIHSILRSEQ ID NO: 803CFFGAIWEFIHSILOSEQ ID NO: 804CFFGAIAEFIHSILSEQ ID NO: 805CIFGAIWEFIHSILSEQ ID NO: 806CGIFGAIWEFIHSILSEQ ID NO: 807CFFGAIWEFIHSILESEQ ID NO: 808CFFGAIWEFIHSILEGSEQ ID NO: 809CFFGAIWEFIHSILEGLSEQ ID NO: 810CFFGAIWEFIHSILEGLISEQ ID NO: 811CFFGAIWEFIHSILEGLIDSEQ ID NO: 812CFFGAIWEFIHSILEGLIDGSEQ ID NO: 813CFFGAIWEFIHSILEGLIEASEQ ID NO: 814CFFGAIWEFIHSILEGLIDWSEQ ID NO: 815CFFGAIWEFIHSILEGLIDGWYGSEQ ID NO: 816CFFGAIWEFIHSILEGLIDGWYGFSEQ ID NO: 817FFGAIWEFIHSILCSEQ ID NO: 818CFWGAIWEFIHSILSEQ ID NO: 819CFFGAIWEFIHSILKGLIDWSEQ ID NO: 820CAFGKIWEFAHSILSEQ ID NO: 821CAFGKIWEFIHSILSEQ ID NO: 822CFFGKIWEFIHSILSEQ ID NO: 823CAFGAIWEFIHSILSEQ ID NO: 824CAFGAIWEFAHSILSEQ ID NO: 825CGFFGAIAGLLHNIFKSEQ ID NO: 826CFFGAIAGLLHNIFKSEQ ID NO: 827CGFFEAIEGLLHNIFKSEQ ID NO: 828CFFEAIAGLLHNIFKSEQ ID NO: 829CFFEAIWGLLHNIFKSEQ ID NO: 830CGFFGAIAELLHNIFKSEQ ID NO: 831CFFGAIAELLHNIFKSEQ ID NO: 832CGFFEAIAELLHNIFKSEQ ID NO: 833CFFEAIAELLHNIFKSEQ ID NO: 834CFFGAIWELLHNIFKSEQ ID NO: 835CFFEAIWELLHNIFKSEQ ID NO: 836CFFGAIWEFIHSILFFGAIWEFIHSILSEQ ID NO: 837CFFGAIWEFIHSILGGGFFGAIWEFIHSILSEQ ID NO: 838CFFGAIWEFIHSILGFFGAIWEFIHSILSEQ ID NO: 839GGLFEALLELLESLWELLLEWSEQ ID NO: 840GGFFEAFFEFFESFWEFFFEASEQ ID NO: 841GGLFEALLELLESLWEGLLEASEQ ID NO: 842CGLFHALLHLLHSLWHLLLHASEQ ID NO: 843CGLFEALLHLLHSLWHLLLEASEQ ID NO: 844CGLFEALLELLHSLWHLLLEASEQ ID NO: 845CGLFEALLHLLESLWHLLLEASEQ ID NO: 846CGLFEALLHLLHSLWELLLEASEQ ID NO: 847CGLFHALLELLHSLWHLLLEASEQ ID NO: 848CGLFHALLHLLESLWHLLLEASEQ ID NO: 849CGLFHALLHLLHSLWELLLEASEQ ID NO: 850CGLFHALLELLESLWHLLLEASEQ ID NO: 851CGLFHALLELLHSLWELLLEASEQ ID NO: 852CGLFHALLHLLESLWELLLEASEQ ID NO: 853CGLFEALLHLLESLWELLLEASEQ ID NO: 854CGLFEALLELLHSLWELLLEASEQ ID NO: 855CGLEALLELLESLWHLLLEASEQ ID NO: 856CGLFHALLELLESLWELLLEASEQ ID NO: 857CFFGAIWEFIHSILHLLLEASEQ ID NO: 858CFFGAIWEFIHSILKLLLEASEQ ID NO: 859CGFFGAIWEFIHSILGFFGAIWEFIHSILSEQ ID NO: 860CFFGAIWEFAHSILFFGAIWEFAHSILSEQ ID NO: 861CFFGAIWEFAHSILGFFGAIWEFAHSILSEQ ID NO: 862CGFFGAIWEFAHSILGFFGAIWEFAHSILSEQ ID NO: 863CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDGSEQ ID NO: 864CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDGWYGSEQ ID NO: 865CFFGAIWEFIHSILGLFEAIEGFIENGWEGMIDGWYGFSEQ ID NO: 866CFFGALLEFIHSILELLLEASEQ ID NO: 867CGLFGALLEFIHSILELLLEASEQ ID NO: 868CGFFGALLEFIHSILELLLEASEQ ID NO: 869CFFGALLEFIHSLWELLLEASEQ ID NO: 870CGLFGALLEFIHSLWELLLEASEQ ID NO: 871CGFFGALLEFIHSLWELLLEASEQ ID NO: 872CIFGAIAGFIKNIWK(stearyl)SEQ ID NO: 873(stearyl) IFGAIAGFIKNIWCSEQ ID NO: 874CFFGAIWEFIKSILK(stearyl)SEQ ID NO: 875(stearyl)FFGAIWEFIKSILCSEQ ID NO: 876CFFGAIWEFIHSILK(stearyl)SEQ ID NO: 877(stearyl)FFGAIWEFIHSILCSEQ ID NO: 878CIFGAIAGFIKNIWEGLIK(stearyl)SEQ ID NO: 879(stearyl)IFGAIAGFIKNIWEGLICSEQ ID NO: 880(stearyl)IFGAIAGFIKNILKGLCSEQ ID NO: 881(stearyl)GIFGAIAGFIKNILKGLCSEQ ID NO: 882CIFGAIAGFIKNILKGLK(stearyl)SEQ ID NO: 883CGLFGAIAGFIVNGWVGMIDGSEQ ID NO: 884CGLFGAIAGFIVNGWVGMIDGWYGSEQ ID NO: 885CGLFEAIEGFIVNGWVGMIDGWYGSEQ ID NO: 886CGLFGAIAGFIVNGWVGMIDGWYGFSEQ ID NO: 887CGLFEAIEAGFIVNGWVGMIDGWYGFSEQ ID NO: 888CGLFGAIAGFIVNGWVGMIDGWYGK(stearyl)SEQ ID NO: 889CGLFEAIEGFIVNGWVGMIDGWYGK(stearyl)SEQ ID NO: 890(stearyl)GLFGAIAGFIVNGWVGMIDGWYGCSEQ ID NO: 891(stearyl)GLFEAIEGFIVNGWVGMIDGWYGCSEQ ID NO: 892(stearyl)GLFGAIAGFIVNGWVGMIDGWYGFCSEQ ID NO: 893(stearyl)GLFEAlEAGFIVNGWVGMIDGWYGFCSEQ ID NO: 894CFFGAIWGLLHSILHSEQ ID NO: 895CFFGAIWELLHSILSEQ ID NO: 896CFFGAIWELLHSILHSEQ ID NO: 897CFFGAIWGLLHSILKSEQ ID NO: 898CFFGAIWELLHSILKSEQ ID NO: 899CGLFGALLHLLHSLWELLLEASEQ ID NO: 900CGLFGALLELLHSLWELLLEASEQ ID NO: 901CFFGAIWEFIHSILELLLEASEQ ID NO: 902CFFGAIWEFIHSILHGLLEASEQ ID NO: 903CFFGAIWEFIHSILEGLLEASEQ ID NO: 904CGFFGAIWEFIHSILHLLLEASEQ ID NO: 905CGFFGAIWEFIHSILELLLEASEQ ID NO: 906CGFFGAIWEFIHSILHGLLEASEQ ID NO: 907CGFFGAIWEFIHSILEGLLEASEQ ID NO: 908CGFFGAIAGLLHSILSEQ ID NO: 909CGFFGAIWGLLHSILSEQ ID NO: 910CGFFGALLGLLHSILSEQ ID NO: 911CFFGAIWEFAKSALSEQ ID NO: 912CIFGAIAGFIHNILKGLSEQ ID NO: 913CFFGAIAGFIKNILKGLSEQ ID NO: 914CIFGAIWGFIKNILKGLSEQ ID NO: 915CIFGAIWGFIHNILKGLSEQ ID NO: 916CIFGAIAGLLKNILKGLSEQ ID NO: 917CIFGAIAGLLHNILKGLSEQ ID NO: 918CIFEAIAGFIKNILKGLSEQ ID NO: 919CIFEAIAGFIHNILKGLSEQ ID NO: 920CGNFGEIAELIEEGLKNLIDWWNGSEQ ID NO: 921CGFFGEIAELIEEGLENLIDWWNGSEQ ID NO: 922CGNFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 923CGNFGEIAELIEEGLENLIDWWNGSEQ ID NO: 924CGFFGEIEELIEENGENLIDWWNGSEQ ID NO: 925CGFFGAIEELIEEGLKNLIDWWNGSEQ ID NO: 926CGFFGAIAELIEEGLKNLIDWWNGSEQ ID NO: 927CGFFGEIAELIEEGLKNLIDWWNGFSEQ ID NO: 928GFFGEIAELIEEGLKNLIDWWNGCSEQ ID NO: 929GNWWDILNKLGEEILEAIEGFFGCSEQ ID NO: 930CGNWWDILNKLGEEILEAIEGFFGSEQ ID NO: 931CGFLGEIAELIEEGLKNLIDWWNGSEQ ID NO: 932CGFFGEIWELIEEGLKNLIDWWNGSEQ ID NO: 933CGFFGEIAELWEEGLKNLIDWWNGSEQ ID NO: 934CGFFGEIAELIWEGLKNLIDWWNGSEQ ID NO: 935CGFFGEIAELIEWGLKNLIDWWNGSEQ ID NO: 936CGFFGEIAELIEEGLRNLIDWWNGSEQ ID NO: 937CGFFGEIAELIEEGLDNLIDWWNGSEQ ID NO: 938CGFFGEIAELIEEGLKNLNDWWNGSEQ ID NO: 939CGFFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 940CGFLGEIEELIEEGLKNLIDWWNGSEQ ID NO: 941CGFFGLIEELIEEGLKNLIDWWNGSEQ ID NO: 942CGFFGEIAELIEEGLKNLIDWWNGK(stearyl)SEQ ID NO: 943(stearyl)GFFGEIAELIEEGLKNLIDWWNGCSEQ ID NO: 944CFFGAIWEFAKSILK(stearyl)SEQ ID NO: 945CGFFGAIWEFAKSILSEQ ID NO: 946CFFGKIWEFIKSILK(stearyl)SEQ ID NO: 947(stearyl)FFGKIWEFIKSILCSEQ ID NO: 948CFFGAIWEFIKSIAK(stearyl)SEQ ID NO: 949(stearyl)FFGAIWEFIKSIACSEQ ID NO: 950(stearyl)FFGAIWEFAKSILCSEQ ID NO: 951CFFGGIWEFIKSILK(stearyl)SEQ ID NO: 952(stearyl)FFGGIWEFIKSILCSEQ ID NO: 953CFFKAIWEFIKSILK(stearyl)SEQ ID NO: 954(stearyl)FFKAIWEFIKSILCSEQ ID NO: 955CFFGAIWEAIKSILK(stearyl)SEQ ID NO: 956(stearyl)FFGAIWEAIKSILCSEQ ID NO: 957CFFKAIWEFAKSILSEQ ID NO: 958CFFKAIWEFAHSILSEQ ID NO: 959CFFKAIWEFAKSILK(stearyl)SEQ ID NO: 960(stearyl)FFKAIWEFAKSILCSEQ ID NO: 961CFFKAIWEFAHSILK(stearyl)SEQ ID NO: 962CGLFGEIAELIEEGLENLIDWWNGSEQ ID NO: 963CGLFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 964CFFGAIWEFAKSILK(stearyl)SEQ ID NO: 965CGLFGEIEELIEEGLKGLIDWWNGSEQ ID NO: 966CGLFGEIAELIEEGLKNLIDWWNGSEQ ID NO: 967CGLFGEIAELIEEGLEGLIDWWNGSEQ ID NO: 968GLFGEIEELIEEGLENLIDWWNGCSEQ ID NO: 969(stearyl)GLFGEIEELIEEGLENLIDWWNGCSEQ ID NO: 970CGLFGEIEELIEEGLENLIDWWNGK(stearyl)SEQ ID NO: 971CGNWWDILNELGEEILEEIEGFLGSEQ ID NO: 972CALFGEIEELIEEGLENLIDWWNGSEQ ID NO: 973CELFGEIEELIEEGLENLIDWWNGSEQ ID NO: 974CSLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 975CNLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 976CVLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 977CGFFGEIEELIEEGLENLIDWWNGSEQ ID NO: 978CGVFGEIEELIEEGLENLIDWWNGSEQ ID NO: 979CGIFGEIEELIEEGLENLIDWWNGSEQ ID NO: 980CGWFGEIEELIEEGLENLIDWWNGSEQ ID NO: 981CGYFGEIEELIEEGLENLIDWWNGSEQ ID NO: 982CGLLGEIEELIEEGLENLIDWWNGSEQ ID NO: 983CGLVGEIEELIEEGLENLIDWWNGSEQ ID NO: 984CGLIGEIEELIEEGLENLIDWWNGSEQ ID NO: 985CGLWGEIEELIEEGLENLIDWWNGSEQ ID NO: 986CGLYGEIEELIEEGLENLIDWWNGSEQ ID NO: 987CGLFEEIEELIEEGLENLIDWWNGSEQ ID NO: 988CGLFAEIEELIEEGLENLIDW1NNGSEQ ID NO: 989CGLFNEIEELIEEGLENLIDWWNGSEQ ID NO: 990CGLFSEIEELIEEGLENLIDWWNGSEQ ID NO: 991CGLFGAIEELIEEGLENLIDWWNGSEQ ID NO: 992CGLFGDIEELIEEGLENLIDWWNGSEQ ID NO: 993CGLFGNIEELIEEGLENLIDWWNGSEQ ID NO: 994CGLFGSIEELIEEGLENLIDWWNGSEQ ID NO: 995CGLFGELEELIEEGLENLIDWWNGSEQ ID NO: 996CGLFGEVEELIEEGLENLIDWWNGSEQ ID NO: 997CGLFGEFEELIEEGLENLIDWWNGSEQ ID NO: 998CGLFGEWEELIEEGLENLIDWWNGSEQ ID NO: 999CGLFGEYEELIEEGLENLIDWWNGSEQ ID NO: 1000CGLFGEIAELIEEGLENLIDWWNGSEQ ID NO: 1001CGLFGEIGELIEEGLENLIDWWNGSEQ ID NO: 1002CGLFGEILELIEEGLENLIDWWNGSEQ ID NO: 1003CGLFGEIVELIEEGLENLIDWWNGSEQ ID NO: 1004CGLFGEISELIEEGLENLIDWWNGSEQ ID NO: 1005CGLFGEIEDLIEEGLENLIDWWNGSEQ ID NO: 1006CGLFGEIENLIEEGLENLIDWWNGSEQ ID NO: 1007CGLFGEIESLIEEGLENLIDWWNGSEQ ID NO: 1008CGLFGEIEALIEEGLENLIDWWNGSEQ ID NO: 1009CGLFGEIEGLIEEGLENLIDWWNGSEQ ID NO: 1010CGLFGEIEEVIEEGLENLIDWWNGSEQ ID NO: 1011CGLFGEIEEIIEEGLENLIDWWNGSEQ ID NO: 1012CGLFGEIEEFIEEGLENLIDWWNGSEQ ID NO: 1013CGLFGEIEEAIEEGLENLIDWWNGSEQ ID NO: 1014CGLFGEIEEYIEEGLENLIDWWNGSEQ ID NO: 1015CGLFGEIEEWIEEGLENLIDWWNGSEQ ID NO: 1016CGLFGEIEELVEEGLENLIDWWNGSEQ ID NO: 1017CGLFGEIEELLEEGLENLIDWWNGSEQ ID NO: 1018CGLFGEIEELFEEGLENLIDWWNGSEQ ID NO: 1019CGLFGEIEELAEEGLENLIDWWNGSEQ ID NO: 1020CGLFGEIEELYEEGLENLIDWWNGSEQ ID NO: 1021CGLFGEIEELWEEGLENLIDWWNGSEQ ID NO: 1022CGLFGEIEELIDEGLENLIDWWNGSEQ ID NO: 1023CGLFGEIEELINEGLENLIDWWNGSEQ ID NO: 1024CGLFGEIEELISEGLENLIDWWNGSEQ ID NO: 1025CGLFGEIEELIEDGLENLIDWWNGSEQ ID NO: 1026CGLFGEIEELIEYGLENLIDWWNGSEQ ID NO: 1027CGLFGEIEELIESGLENLIDWWNGSEQ ID NO: 1028CGLFGEIEELIEQGLENLIDWWNGSEQ ID NO: 1029CGLFGEIEELIENGLENLIDWWNGSEQ ID NO: 1030CGLFGEIEELIEEALENLIDWWNGSEQ ID NO: 1031CGLFGEIEELIEENLENLIDWWNGSEQ ID NO: 1032CGLFGEIEELIEESLENLIDWWNGSEQ ID NO: 1033CGLFGEIEELIEEQLENLIDWWNGSEQ ID NO: 1034CGLFGEIEELIEEGWENLIDWWNGSEQ ID NO: 1035CGLFGEIEELIEEGVENLIDWWNGSEQ ID NO: 1036CGLFGEIEELIEEGIENLIDWWNGSEQ ID NO: 1037CGLFGEIEELIEEGFENLIDWWNGSEQ ID NO: 1038CGLFGEIEELIEEGAENLIDWWNGSEQ ID NO: 1039CGLFGEIEELIEEGYENLIDWWNGSEQ ID NO: 1040CGLFGEIEELIEEGLRNLIDWWNGSEQ ID NO: 1041CGLFGEIEELIEEGLHNLIDWWNGSEQ ID NO: 1042CGLFGEIEELIEEGLONLIDWWNGSEQ ID NO: 1043CGLFGEIEELIEEGLDNLIDWWNGSEQ ID NO: 1044CGLFGEIEELIEEGLKNLIDWWNGSEQ ID NO: 1045CGLFGEIEELIEEGLEGLIDWWNGSEQ ID NO: 1046CGLFGEIEELIEEGLEYLIDWWNGSEQ ID NO: 1047CGLFGEIEELIEEGLEQLIDWWNGSEQ ID NO: 1048CGLFGEIEELIEEGLESLIWWNGSEQ ID NO: 1049CGLFGEIEELIEEGLEALIDWWNGSEQ ID NO: 1050CGLFGEIEELIEEGLE(Cit)LIDWWNGSEQ ID NO: 1051CGLFGEIEELIEEGLENMIDWWNGSEQ ID NO: 1052CGLFGEIEELIEEGLENFIDWWNGSEQ ID NO: 1053CGLFGEIEELIEEGLENIIDWWNGSEQ ID NO: 1054CGLFGEIEELIEEGLENWIDWWNGSEQ ID NO: 1055CGLFGEIEELIEEGLENVIDWWNGSEQ ID NO: 1056CGLFGEIEELIEEGLENYIDWWNGSEQ ID NO: 1057CGLFGEIEELIEEGLEN(NIe)IDVWWNGSEQ ID NO: 1058CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1059CGLFGEIEELIEEGLENLVDWWNGSEQ ID NO: 1060CGLFGEIEELIEEGLENLFDWWNGSEQ ID NO: 1061CGLFGEIEELIEEGLENLWDWWNGSEQ ID NO: 1062CGLFGEIEELIEEGLENLYDWWNGSEQ ID NO: 1063CGLFGEIEELIEEGLENLIEWWNGSEQ ID NO: 1064CGLFGEIEELIEEGLENLINWWNGSEQ ID NO: 1065CGLFGEIEELIEEGLENLISWWNGSEQ ID NO: 1066CGLFGEIEELIEEGLENLIQWWNGSEQ ID NO: 1067CGLFGEIEELIEEGLENLIDGWNGSEQ ID NO: 1068CGLFGEIEELIEEGLENLIDAWNGSEQ ID NO: 1069CGLFGEIEELIEEGLENLIDFWNGSEQ ID NO: 1070CGLFGEIEELIEEGLENLIDLWNGSEQ ID NO: 1071CGLFGEIEELIEEGLENLIDIWNGSEQ ID NO: 1072CGLFGEIEELIEEGLENLIDVWNGSEQ ID NO: 1073CGLFGEIEELIEEGLENLIDWGNG all (D)SEQ ID NO: 1074CGLFGEIEELIEEGLENLIDWANGSEQ ID NO: 1075CGLFGEIEELIEEGLENLIDWFNGSEQ ID NO: 1076CGLFGEIEELIEEGLENLIDWINGSEQ ID NO: 1077CGLFGEIEELIEEGLENLIDWVNGSEQ ID NO: 1078CGLFGEIEELIEEGLENLIDWYNGSEQ ID NO: 1079CGLFGEIEELIEEGLENLIDIWWQGSEQ ID NO: 1080CGLFGEIEELIEEGLENLIDWWTGSEQ ID NO: 1081CGLFGEIEELIEEGLENLIDWWSGSEQ ID NO: 1082CGLFGEIEELIEEGLENLIDWWEGSEQ ID NO: 1083CGLFGEIEELIEEGLENLIDWW(Cit)GSEQ ID NO: 1084CGLFGEIEELIEEGLENLIDWWNASEQ ID NO: 1085CGLFGEIEELIEEGLENLIDWWNNSEQ ID NO: 1086CGLFGEIEELIEEGLENLIDWWNSSEQ ID NO: 1087CGLFGEIEELIEEGLENLIDWWNYSEQ ID NO: 1088CGLFGEIEELIEEGLENLIDWWNWSEQ ID NO: 1089CFFGAIWGLLHSILSEQ ID NO: 1090CFFGK(stearyl) IWEFI KSI LSEQ ID NO: 1091CFFGK( stearyl)IWEFIHSILSEQ ID NO: 1092CFFK(stearyl )AIWEFIKSILSEQ ID NO: 1093CGFFGAIWGLLHSILKSEQ ID NO: 1094CGFFEAIWGLLHSILSEQ ID NO: 1095CFFGAIWGLLKSILSEQ ID NO: 1096CGFFGAIWGLLKSILSEQ ID NO: 1097CFFEAIWGLLKSILSEQ ID NO: 1098CGFFEAIWGLLKSILSEQ ID NO: 1099CFFGAIWGLLHSILKGLIDWWNGSEQ ID NO: 1100CFFGAIWGLLHSILKGLIDGWYGSEQ ID NO: 1101CGIFGAIAGLLKNIFKGSEQ ID NO: 1102CGIFGAIAGLLKNIFKASEQ ID NO: 1103CGIFGAIAGLLKNIFKLSEQ ID NO: 1104CGIFGAIAGLLKNIFKWSEQ ID NO: 1105CGIFGAIAGLLKNIFKFSEQ ID NO: 1106CGIFGAIAGLLKNIFKNSEQ ID NO: 1107CGIFGAIAGLLKNIFKESEQ ID NO: 1108CGIFGAIAGLLKNIFKSSEQ ID NO: 1109CGIFGAIAGLLKNIFK(stearyl)SEQ ID NO: 1110CGIFGAIAGLLKNIFKK(stearyl)SEQ ID NO: 1111(stearyl)GIFGAIAGLLKNIFKCSEQ ID NO: 1112CGIFGAIAGLLKNIFK(lauryl)SEQ ID NO: 1113CGIFGAIAGLLKNIFKK(lauryl)SEQ ID NO: 1114(lauryl)GIFGAIAGLLKNIFKCSEQ ID NO: 1115CGIFGAIAGLLHNIFKSEQ ID NO: 1116CGIFGAIAGLLONIFKSEQ ID NO: 1117CGIFGAIAGLLRNIFKSEQ ID NO: 1118CGIFGAIAGLLENIFKSEQ ID NO: 1119CGIFGAIAGLLDNIFKSEQ ID NO: 1120CGIFGAIAGLLKNIFHSEQ ID NO: 1121CGIFGAIAGLLKNIFOSEQ ID NO: 1122CGIFGAIAGLLKINFESEQ ID NO: 1123CGIFGAIAGLLKNIFDSEQ ID NO: 1124CGIFGAIAGLLKNIFNSEQ ID NO: 1125CGIFGAIAGLLNNIFKSEQ ID NO: 1126CGIFGIAIGLLKNIFKGIFGAIAGLLKNIFKSEQ ID NO: 1127CGIFGAIWGLLKNIFKGSEQ ID NO: 1128CGIFGAIWGLLKNIFKASEQ ID NO: 1129CGIFGAIWGLLKNIFKLSEQ ID NO: 1130CGIFGAIWGLLKNIFKWSEQ ID NO: 1131CGIFGAIWGLLKNIFKFSEQ ID NO: 1132CGIFGAIWGLLKNIFKNSEQ ID NO: 1133CGIFGAIWGLLKNIFKESEQ ID NO: 1134CGIFGAIWGLLKNIFKSSEQ ID NO: 1135CGIFGAIWGLLKNIFK(stearyl)SEQ ID NO: 1136CGIFGAIWGLLKNIFKK(stearyl)SEQ ID NO: 1137(stearyl)GIFGAIWGLLKNIFKCSEQ ID NO: 1138CGIFGAIWGLLKNIFK(lauryl)SEQ ID NO: 1139CGIFGAIWGLLKNIFKK(lauryl)SEQ ID NO: 1140(lauryl)GIFGAIWGLLKNIFKCSEQ ID NO: 1141CGIFGAIWGLLHNIFKSEQ ID NO: 1142CGIFGAIWGLLONIFKSEQ ID NO: 1143CGIFGAIWGLLRNIFKSEQ ID NO: 1144CGIFGAIWGLLENIFKSEQ ID NO: 1145CGIFGAIWGLLDNIFKSEQ ID NO: 1146CGIFGAIWGLLKNIFHSEQ ID NO: 1147CGIFGAIWGLLKNIFOSEQ ID NO: 1148CGIFGAIWGLLKINFESEQ ID NO: 1149CGIFGAIWGLLKNIFDSEQ ID NO: 1150CGIFGAIWGLLKNIFNSEQ ID NO: 1151CGIFGAIWGLLNNIFKSEQ ID NO: 1152CFFGAIWGLLKNIFKSEQ ID NO: 1153CGFFGAIWGLLKNIFKSEQ ID NO: 1154CIFGAIWGLLKNIFKSEQ ID NO: 1155CGIFGAIWIGLLKNIFKGIFGAIWGLLKNIFKSEQ ID NO: 1156CGIFGAIWGLLHNIFHSEQ ID NO: 1157CGIFGAIWGLLONIFOSEQ ID NO: 1158CGIFGAIAGLLHSILKSEQ ID NO: 1159CGIFGAIWGLLHSILKSEQ ID NO: 1160CGIFGAIAGLLHSILSEQ ID NO: 1161CGIFGAIWGLLHSILSEQ ID NO: 1162CGIFGAIWELLKNIFKSEQ ID NO: 1163CGIFGAIWGLLHNIFHGIFGAIWGLLHNIFKSEQ ID NO: 1164CGIFEAIWGLLHNIFHGIFEAIWGLLHNIFHSEQ ID NO: 1165CGIFEAIWGLLKNIFHGIFEAIWGLLHNIFHSEQ ID NO: 1166CGIFEAIWGLLKNIFKGIFEAIWELLKNIFHSEQ ID NO: 1167CGIFEAIWGLLKNIFHGIFEAIWGLLKNIFHSEQ ID NO: 1168CGLFEALLELLESLWELLLEAWNGSEQ ID NO: 1169CGLFEALLELLESLWELLLEWWNGSEQ ID NO: 1170CGLFGELEELLEEGLENLLDWWNGSEQ ID NO: 1171CGLFGELEELLEEGLENLLEWWNGSEQ ID NO: 1172CGLFGELEELLEEGWELLLEAWNGSEQ ID NO: 1173CGLFGELEELLEEGWELLLEWWNGSEQ ID NO: 1174CGLFGELEELLEEGWELLLDWWNGSEQ ID NO: 1175CGLFGALLELLEEGLENLIDWWNGSEQ ID NO: 1176CGLFEALLELLEEGLENLIDWWNGSEQ ID NO: 1177CGLFEALLELLESLLENLIDWWNGSEQ ID NO: 1178CGLFGELAELLEEGLENLLDWWNGSEQ ID NO: 1179GLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1180CFFGNIWEFIHSILSEQ ID NO: 1181CFFGAIWNFIHSILSEQ ID NO: 1182CFFGNIWNFIHSILSEQ ID NO: 1183CGIFGNIWNFIKNIFKSEQ ID NO: 1184CGIFGNIWNLLKNIFKSEQ ID NO: 1185CGIFGNIWGLLKNIFKSEQ ID NO: 1186CGIFGNIWNFIKNIFHSEQ ID NO: 1187CGIFGNIWNLLKNIFHSEQ ID NO: 1188CGIFGNIWGLLKNIFHSEQ ID NO: 1189CGIFENIWNFIKNIFKSEQ ID NO: 1190CGIFENIWNFIKNIFHSEQ ID NO: 1191CGIFENIWGLLKNIFKSEQ ID NO: 1192CGIFENIWGLLKNIFHSEQ ID NO: 1193CGIFENIWNLLKNIFKSEQ ID NO: 1194CGIFENIWNLLKNIFHSEQ ID NO: 1195CGLFGAIAGLLENIFENLIDWWNGSEQ ID NO: 1196CGLFGAIAGLLNKIFKNLIDWWNGSEQ ID NO: 1197CGLFGAIAGLLENIFKNLLIDWWNGSEQ ID NO: 1198CGLFGAIAGLLKNIFENLIDWWNGSEQ ID NO: 1199CGLFGAIAGLLKNIFHNLIDWWNGSEQ ID NO: 1200CLIGAILKVLATGLPTLISWIKNKRKQSEQ ID NO: 1201CGLLEEIEELLEEGLENLIDWWNGSEQ ID NO: 1202CGLFEELEELLEEGLENLIDWWNGSEQ ID NO: 1203CGLFEELEELLEEGLENLIEASEQ ID NO: 1204CGLFEELEELLEEGLENLIEAWNGSEQ ID NO: 1205CGLFEELEELLEEGLENLIEWSEQ ID NO: 1206CGLFEELEELLEEGLENLIEWWNGSEQ ID NO: 1207CGLFEELEELLEEGLENLIDASEQ ID NO: 1208CGLFEELEELLEEGLENLIDAWNGSEQ ID NO: 1209CGLFEELEELLEEGLENLIDWSEQ ID NO: 1210CFLGALKFALKSLLSEQ ID NO: 1211CFLGALHFALKSLLSEQ ID NO: 1212CFLGALKFALHSLLSEQ ID NO: 1213CFLGALHFALHSLLSEQ ID NO: 1214FLGALKFALKSLLCSEQ ID NO: 1215GFLGALKFALKSLLCSEQ ID NO: 1216CGLFGELEELIEEGLENLLDWWNGSEQ ID NO: 1217CGLFGEIEELLEEGLENLLDWWNGSEQ ID NO: 1218CGLFGELEELLEEGLENLIDWWNGSEQ ID NO: 1219CGLFGEIEELIEEGLENLMDWWNGSEQ ID NO: 1220CGLFGEIEELIEEGLENLEDWWNGSEQ ID NO: 1221CGLFGEIEELIEEGLENLDDWWNGSEQ ID NO: 1222CGLFGEIEELIEEGLENLNDWWNGSEQ ID NO: 1223CGLFGEIEELIEEGLENLSDWWNGSEQ ID NO: 1224CGLFGEIEELIEEGLENLQDWWNGSEQ ID NO: 1225CGLFGEIEELIEEGLENL-CIT-DWWNGSEQ ID NO: 1226CGLFGEIEELIEELLENLIDWWNGSEQ ID NO: 1227CGLFGEIEELIEEILENLIDWWNGSEQ ID NO: 1228CGLFGEIEELIEEVLENLIDWWNGSEQ ID NO: 1229CFLGALWKLLSHLLSEQ ID NO: 1230CFLGALWKILSHLLSEQ ID NO: 1231CFLGALWVKVLSHLLSEQ ID NO: 1232CFLGALWKFLSHLLSEQ ID NO: 1233CFLEALWKALSHLLSEQ ID NO: 1234CFLHALWKALSHLLSEQ ID NO: 1235CFLKALWKALSHLLSEQ ID NO: 1236CFLNALWKALSHLLSEQ ID NO: 1237CFLSALWKALSHLLSEQ ID NO: 1238CFLQALWKALSHLLSEQ ID NO: 1239CFLEALWEALSHLLSEQ ID NO: 1240CFLGALWEALSHLLSEQ ID NO: 1241CFLEALWKLLSHLLSEQ ID NO: 1242CFLEALWEALEELLSEQ ID NO: 1243CFLEELWEALEELLSEQ ID NO: 1244CFLEALWEALEHLLSEQ ID NO: 1245CFLEELWEALEHLLSEQ ID NO: 1246CFLEELWELLEELLSEQ ID NO: 1247CFLEELWELLEHLLSEQ ID NO: 1248CGLFGEIEELLEEGLE-CIT-LIDWWNGSEQ ID NO: 1249CGLFEEIEELLEEGLE-CIT-LIDWWNGSEQ ID NO: 1250CGLFGEIAELLEEGLE-CIT-LIDWWNGSEQ ID NO: 1251CGLFEEIAELLEEGLE-CIT-LIDWWNGSEQ ID NO: 1252CGLFGEIEELLEEGLE-CIT-LVDWWNGSEQ ID NO: 1253CGLFEEIEELLEEGLE-CIT-LVDWWNGSEQ ID NO: 1254CGLFGEIAELLEEGLE-CIT-LVDWWNGSEQ ID NO: 1255CGLFEEIAELLEEGLE-CIT-LVDWWNGSEQ ID NO: 1256CGLFGEIEELLEEGLE-CIT-LIDWWNESEQ ID NO: 1257CGLFEEIEELLEEGLE-CIT-LIDWWNESEQ ID NO: 1258CGLFGEIAELLEEGLE-CIT-LIDWWNESEQ ID NO: 1259CGLFEEIAELLEEGLE-CIT-LIDWWNESEQ ID NO: 1260CGLFGEIEELLEEGLH-CIT-LIDWWNGSEQ ID NO: 1261CGLFEEIEELLEEGLH-CIT-LIDWWNGSEQ ID NO: 1262CGLFGEIAELLEEGLH-CIT-LIDWWNGSEQ ID NO: 1263CGLFEEIAELLEEGLH-CIT-LIDWWNGSEQ ID NO: 1264CGLFGEIEELLEEGLE-CIT-LVDWWNESEQ ID NO: 1265CGLFEEIEELLEEGLE-CIT-LVDWWNESEQ ID NO: 1266CGLFGEIAELLEEGLE-CIT-LVDWWNESEQ ID NO: 1267CGLFEEIAELLEEGLE-CIT-LVDWWNESEQ ID NO: 1268CFFKNIWEFIKSILSEQ ID NO: 1269CFFKNIWNFIKSILSEQ ID NO: 1270CFFKAIWEFIKSILESEQ ID NO: 1271CFFKAIWEFIKNIFKSEQ ID NO: 1272CFFKAIWEFIKNIFKESEQ ID NO: 1273CFFKAIWELLKSILSEQ ID NO: 1274CFFKAIWGLLKSILSEQ ID NO: 1275CFFKAIWEFIKSILKSEQ ID NO: 1276CFFKNIWGLLKSILSEQ ID NO: 1277CFFKAIWGLLKNIFKSEQ ID NO: 1278CFFKAIWELLKNIFKSEQ ID NO: 1279CFFKNIWGLLKNIFKSEQ ID NO: 1280CFFKNIWELLKNIFKSEQ ID NO: 1281CFFKAIWEFIRSILSEQ ID NO: 1282CFFKAIWEFIKSLLSEQ ID NO: 1283CFFKAIWEFIKSALSEQ ID NO: 1284CFFKAIWEFIKSIFSEQ ID NO: 1285CFFKALWEFLKSLLSEQ ID NO: 1286CIFKAIWEFIKSILSEQ ID NO: 1287CFFKAIWEFIKSIWSEQ ID NO: 1288CFFHAIWEFIKSILSEQ ID NO: 1289CFFEAIWEFIKSILSEQ ID NO: 1290CFFKAIAEFIKSILSEQ ID NO: 1291CFFKAIEEFIKSILSEQ ID NO: 1292CFFKAILEFIKSILSEQ ID NO: 1293CFFKAIFEFIKSILSEQ ID NO: 1294CFFKAIWGFIKSILSEQ ID NO: 1295CFFKAIWHFIKSILSEQ ID NO: 1296CFFKAIWKFIKSILSEQ ID NO: 1297CFFEAIWKFIKSILSEQ ID NO: 1298CFFKAIWELIKSILSEQ ID NO: 1299CFFKALWELLKSLLSEQ ID NO: 1300CFFKAIWEAIKSILSEQ ID NO: 1301CFFKAIWEFLKSILSEQ ID NO: 1302CFFKAIWEFIHSILSEQ ID NO: 1303CFFKAIWEFIESILSEQ ID NO: 1304CFFKAIWEFIKNILSEQ ID NO: 1305CFFKAIWEFIKWILSEQ ID NO: 1306CFFKAIWEFIKEILSEQ ID NO: 1307CFFKAIWEFIKGILSEQ ID NO: 1308CFFKAIWEFIKSGLSEQ ID NO: 1309CFFKAIWEFIKSIISEQ ID NO: 1310CFFKAIWEFIK-CIT-ILSEQ ID NO: 1311CFFKAIWEFIKSIASEQ ID NO: 1312CFFKAIWEFIKQILSEQ ID NO: 1313CGFFKAIWEFIKSILSEQ ID NO: 1314CFFKAIWEFIKSILKGLIDGSEQ ID NO: 1315CFFKAIWEFIKSILKGLIDGWYGSEQ ID NO: 1316CFFKAIWEFIKSILEGLIDGSEQ ID NO: 1317CFFKAIWEFIKSILEGLIDGWYGSEQ ID NO: 1318CFFKAIWEFIKNIFKGLIDGSEQ ID NO: 1319CFFKAIWEFIKNIFKGLIDGWYGSEQ ID NO: 1320CFFGNIWEFIKSILKGLIDGSEQ ID NO: 1321CFFGNIWEFIKSILKGLIDGWYGSEQ ID NO: 1322CFFGNIWEFIKSILEGLIDGSEQ ID NO: 1323CFFGNIWEFIKSILEGLIDGWYGSEQ ID NO: 1324CFFGNIWEFIKNIFKGLIDGSEQ ID NO: 1325CFFGNIWEFIKNIFKGLIDGEYGSEQ ID NO: 1326CFFKAIWGLLKSILKGLIDGSEQ ID NO: 1327CFFKAIWGLLKSILKGLIDGWYGSEQ ID NO: 1328CFFKAIWGLLKSILEGLIDGSEQ ID NO: 1329CFFKAIWGLLKSILEGLIDGWYGSEQ ID NO: 1330CFFKAIWGLLKNIFKGLIDGSEQ ID NO: 1331CFFKAIWGLLKNIFKGLIDGWYGSEQ ID NO: 1332CFFKAIWGLLKNIFEGLIDGSEQ ID NO: 1333CFFKAIWGLLKNIFEGLIDGWYGSEQ ID NO: 1334CFFKAIWEFIKSILKGLIDGWNGSEQ ID NO: 1335CFFKAIWEFIKNIFKGLIDGWNGSEQ ID NO: 1336CIFGAIAGLLKNILKGLIDGSEQ ID NO: 1337CIFGAIAGLLKNILKGLIDGWYGSEQ ID NO: 1338CFLEALWKALEHLLSEQ ID NO: 1339CFLEALWEALSKLLSEQ ID NO: 1340CFLEALWEALEKLLSEQ ID NO: 1341CFLEALWEALEHLLK(stearyl)SEQ ID NO: 1342(stearyl)FLEALWEALEHLLCSEQ ID NO: 1343(stearyl)GFLEALWEALEHLLCSEQ ID NO: 1344CFLEALWKALSKLLSEQ ID NO: 1345CFLEALWEALDHLLSEQ ID NO: 1346CFLEALWEALTHLLSEQ ID NO: 1347CFLEALWEALNHLLSEQ ID NO: 1348CFLEALWEALQHLLSEQ ID NO: 1349CFLEALWEALEHLLHSEQ ID NO: 1350CFLEALWEALEHLLKSEQ ID NO: 1351CFLEALWEALEHLLESEQ ID NO: 1352CWLEALEALEHLLSEQ ID NO: 1353CLLEALWEALEHLLSEQ ID NO: 1354CFFEALWEALEHLLSEQ ID NO: 1355CFLEALEEALEHLLSEQ ID NO: 1356CFLEALAEALEHLLSEQ ID NO: 1357CFLEALFEALEHLLSEQ ID NO: 1358CLFEALWEALHHLLSEQ ID NO: 1359CLFEALWEALKHLLSEQ ID NO: 1360CFLEALWEALEHGLSEQ ID NO: 1361CLFEALWEALEHLFSEQ ID NO: 1362CLFEALWEALEHFLSEQ ID NO: 1363CLFEALWEALEHLLEGLIDWWYGSEQ ID NO: 1364CLFEALWEALEHLLEGLIDWWNGSEQ ID NO: 1365CLFEALWEALEHLLENLIDWWNGSEQ ID NO: 1366CFLEELWELLEKLLSEQ ID NO: 1367CFLEELWELLEELLESEQ ID NO: 1368CFLEELWELLEELLELLESEQ ID NO: 1369CFLEELWELLEHLLELLDSEQ ID NO: 1370CFLEELWELLEELLELIDSEQ ID NO: 1371CFLEELWELLEELLELLDSEQ ID NO: 1372CFLEELWELLEHLLEGLESEQ ID NO: 1373CFLEELWELLEHLLEGLDSEQ ID NO: 1374CFLEELWELLEHLLEEGLISEQ ID NO: 1375CFLEELWELLEHLLEGLIDWWYGSEQ ID NO: 1376CFLEELWELLEHLLENLIDWWNGSEQ ID NO: 1377CFLEALWEALEHLLELLDSEQ ID NO: 1378CGLFGELEELLEEGLENLTDWWNGSEQ ID NO: 1379CGLFGELEELLEEGLENL-(ALLO-I)-DWWNGSEQ ID NO: 1380CFLEALWEALEHLLELIDSEQ ID NO: 1381CELFEELEELLEEGLENLIDWWNGSEQ ID NO: 1382CGLFEELEELLEEGLELLIDWWNGSEQ ID NO: 1383CGLFEELEELLEEGLELLIDWWNKSEQ ID NO: 1384CGLFEELEELLEEGLENLIDWWNKSEQ ID NO: 1385CGLFGELEELLEEGLENLIDWWNQSEQ ID NO: 1386CGLFGELEELLEEGLENLIDWWNESEQ ID NO: 1387CGLFGELEELLEEGLENLIDWWNNSEQ ID NO: 1388CGLFGELEELLEEGLENLIDWWNSSEQ ID NO: 1389CGLFEELEELLEEGLENLIDWWNQSEQ ID NO: 1390AC-CFLEELWELLEHLLSEQ ID NO: 1391AC-CFLEELWELLEELLSEQ ID NO: 1392CGLLGEIEELLEEGLENLIDWWNGSEQ ID NO: 1393CGLLAEIEELLEEGLENLIDWWNGSEQ ID NO: 1394CGLLGEIEELLEEGLENLIDWWNQSEQ ID NO: 1395CGLLAEIEELLEEGLENLIDWWNQSEQ ID NO: 1396CGLLEEIEELLEEGLENLIDWWNQSEQ ID NO: 1397CGLLGEIEELLEEGLENLIDWWNESEQ ID NO: 1398CGLLAEIEELLEEGLENLIDWWNESEQ ID NO: 1399CGLLEEIEELLEEGLENLIDWWNESEQ ID NO: 1400CGLLGEIEELLEEGLENLIDWWNSSEQ ID NO: 1401CGLLAEIEELLEEGLENLIDWWNSSEQ ID NO: 1402CGLLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1403CGLFAELEELLEEGLENLLEWWNGSEQ ID NO: 1404CGLFEELEELLEEGLENLLEWWNGSEQ ID NO: 1405CGLFGELEELLEEGLENLLEWWNESEQ ID NO: 1406CGLFAELEELLEEGLENLLEWWNESEQ ID NO: 1407CGLFEELEELLEEGLENLLEWWNESEQ ID NO: 1408CGLLGELEELLEEGLENLLEWWNGSEQ ID NO: 1409CGLLGELEELLEEGLENLLEWWNESEQ ID NO: 1410CGILGEIEELLEEGLENLIDWWNGSEQ ID NO: 1411CGILGEIEELLEEGLENLIDWWNESEQ ID NO: 1412CGILGEIEELLEEGLENLIDWWNSSEQ ID NO: 1413CGILAEIEELLEEGLENLIDWWNGSEQ ID NO: 1414CGILEEIEELLEEGLENLIDWWNGSEQ ID NO: 1415CIFGAIAELLKNIFKSEQ ID NO: 1416CIFGAIAELLENIFKSEQ ID NO: 1417CIFGAIAGLLENIFKSEQ ID NO: 1418CFLEELWGLLEHLLSEQ ID NO: 1419CGILAEIEELLEEGLENLIDWWNQSEQ ID NO: 1420CGILAEIEELLEEGLENLIDWWNESEQ ID NO: 1421CGLFAEIEELLEEGLENLIDWWNQSEQ ID NO: 1422CGLFAEIEELLEEGLENLIDWWNESEQ ID NO: 1423CGLFGELEELLEEGLENLLEWWNQSEQ ID NO: 1424CGLFAEIAELLEEGLE-CIT-LIDWWNESEQ ID NO: 1425CGILAEIEELLEEGLENLLEWWNGSEQ ID NO: 1426CGILEEIEELLEEGLENLIDWWNESEQ ID NO: 1427CGILEEIEELLEEGLENLIDWWNQSEQ ID NO: 1428CGLFGEIEELIWEGLENLIDWWNGSEQ ID NO: 1429CGLFGEIAELIWEGLENLIDWWNGSEQ ID NO: 1430CGLFEEIAELIEEGLENLIDWWNGSEQ ID NO: 1431CGLFEEIAELIWEGLENLIDWWNGSEQ ID NO: 1432CELFEEIAELIWEGLENLIDWWNGSEQ ID NO: 1433CELFEEIAELLWEGLENLIDWWNGSEQ ID NO: 1434CGLFEEIAELLWEGLENLIDWWNGSEQ ID NO: 1435CGLFEELAELLWEGLENLIDWWNGSEQ ID NO: 1436CELFEELAELLWEGLENLIDWWNGSEQ ID NO: 1437CELFEELAELLWEGLENLIDWWNSSEQ ID NO: 1438CGLFEELAELLWEGLENLIDWWNSSEQ ID NO: 1439CGIFEELAELLWEGLENLIDWWNGSEQ ID NO: 1440CGIFEELAELLWEGLENLIDWWNSSEQ ID NO: 1441CGLFEELEELLEELLENLIDWWNSSEQ ID NO: 1442CELFEELEELLEELLENLIDWWNSSEQ ID NO: 1443CELFEELEELLEELLELLIDWWNSSEQ ID NO: 1444CEFLEELEELLEELLENLIDWWNSSEQ ID NO: 1445CELFEELEELLEHLLENLIDWWNSSEQ ID NO: 1446CELFEELEELLHELLENLIDWWNSSEQ ID NO: 1447CGLFGELEELLWEGLENLIDWWNGSEQ ID NO: 1448CGLFGELEELLWEGLHNLIDWWNGSEQ ID NO: 1449CGLFGELWELLEHGLENLIDWWNGSEQ ID NO: 1450CGL-R6H-GELEEL-S7H-EEGLENLIDWWNGSEQ ID NO: 1451CGLFEAIEGFIENGWEGMIDGWNGSEQ ID NO: 1452CGLFEAIEGFIENGWEGMIDWWNGSEQ ID NO: 1453CGLFGAIEGFIENGWEGMIDWWNGSEQ ID NO: 1454CGLFAEIEELLEEGLENLLEWWNGSEQ ID NO: 1455CGLFAELEELLEEGLENLIDWWNGSEQ ID NO: 1456CGIFAEIEELLEEGLENLIDWWNGSEQ ID NO: 1457CGLFAEIEELLEEGLENLIDWWNGFSEQ ID NO: 1458CGLFAEIEELLEEGLENLIDWWNASEQ ID NO: 1459CGLFAEIEELLEEGLENLIDWWNSSEQ ID NO: 1460CGLFAEIEELLEEGLENLIDWWN-CITSEQ ID NO: 1461CGLFGEIAGLLEEGLHNLIDWWNGSEQ ID NO: 1462CGLFGEIAGLLEQGLHNLIDWWNGSEQ ID NO: 1463CGLFGEIAGLLESGLHNLIDWWNGSEQ ID NO: 1464CGLFAEIAGLLEQGLHNLIDWWNGSEQ ID NO: 1465CGLFAEIAGLLEEGLHNLIDWWNGSEQ ID NO: 1466CGLFAEIAGLLESGLHNLIDWWNGSEQ ID NO: 1467CGIFEAIAGLLEQGLHNLIDWWNGSEQ ID NO: 1468CGLFGAIAELLEEGLHNLIDWWNGSEQ ID NO: 1469CGLFAAIAELLEEGLHNLIDWWNGSEQ ID NO: 1470CGIFEAIAGLLKNIFKNLIDWWNGSEQ ID NO: 1471CGIFGAIWELLEQGLHNLIDWWNGSEQ ID NO: 1472CGLFAELAGLLEQGLHNLIDWWNGSEQ ID NO: 1473CGILAELAGLLEQGLHNLIDWWNGSEQ ID NO: 1474CGLFGEIEELLEHLLSEQ ID NO: 1475CGLFGEIEELLEELLSEQ ID NO: 1476CGLFGEIEELLEEGLSEQ ID NO: 1477CGLFGEIEELLEHGLSEQ ID NO: 1478CGLFHEIEELLEHLLSEQ ID NO: 1479CFLGALWKALSELLESEQ ID NO: 1480CGLFGEIWELLEEGLSEQ ID NO: 1481CGLFGEIWELLEEGLISEQ ID NO: 1482CGLFGEIWELLEELLSEQ ID NO: 1483CGLFEEIEELLEELLESEQ ID NO: 1484CGLFELIEGFIEWGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 1485CIFGAIAGFIKNIWLHLLHHLLHHLHHLLHHLLHLSEQ ID NO: 1486CEALFGKINAIFIGKLSEQ ID NO: 1487CEENWIGLFGGGNIWEEEEILDLLSEQ ID NO: 1488CLELWLEHLFLELESEQ ID NO: 1489CGNFEEIEGFIENGWEGLIDGWYGYGRKKRRQRRSEQ ID NO: 1490CRGKWYMGFGEIKRQGEGRRYGLFEDWIAENRGISEQ ID NO: 1491GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1492GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1493CGFFGEIAGLLENGLHNLIDWWNGSEQ ID NO: 1494CGFFGEIAALLENGLENLIDWWNGSEQ ID NO: 1495CGFFGEIAEFIHSGLKNLIDWWNGSEQ ID NO: 1496CGFFGEIAGLLKNGLKNLIDWWNGSEQ ID NO: 1497CGFFGEIAGFIKNGLKNLIDWWNGSEQ ID NO: 1498CGFFGEIAEFIHSILKNLIDWWNGSEQ ID NO: 1499CGFFGEIAGLLKNILKNLIDWWNGSEQ ID NO: 1500CGFFGEIAGFIKNILKNLIDWWNGSEQ ID NO: 1501CFLGALFHALSELLSEQ ID NO: 1502CFLGALWHALSELLSEQ ID NO: 1503CFLGALWHALSHLLSEQ ID NO: 1504CFLGALWELLSHLLSEQ ID NO: 1505CFLGALWKALSHLLSEQ ID NO: 1506CFLGALWHALSKLLSEQ ID NO: 1507CFLGALFHLLSHLLSEQ ID NO: 1508CFLGALFHLLSELLSEQ ID NO: 1509CFLGALWHLLSHLLSEQ ID NO: 1510CFLGALWHLLSELLSEQ ID NO: 1511CFLGALFHALSHLLESEQ ID NO: 1512CFLGALFHLLSHLLESEQ ID NO: 1513CGLFGALFHALSHLLESEQ ID NO: 1514CFLGALWKALSHLLSEQ ID NO: 1515CGLFAEIEELLEEGLENLIDWWNGSEQ ID NO: 1516CGLFGEIEELIEEGLE-Cit-LIDWWNGSEQ ID NO: 1517CGLFGEIEELIEEGLENLIDWWNESEQ ID NO: 1518CFFGAIWEFIHSILK(stearyl)SEQ ID NO: 1519CIFGAIAGFIKNIWEGLIK(stearyl)SEQ ID NO: 1520CGIFEAIAGLLKNIFK(stearyl)SEQ ID NO: 1521CGIFEAIAGLLKNIFKK(stearyl)SEQ ID NO: 1522CFLGALFHALSHLLSEQ ID NO: 1523Ac-CIFGAIAGFIKNILKGLIDGSEQ ID NO: 1524CIFGAIAGFIKNILKGLK(stearyIL)SEQ ID NO: 1525Ac-CIFGAIAGFIKNILKGLK(stearyl)SEQ ID NO: 1526CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1527CFLGALWKALSELLKNLIDWWNGSEQ ID NO: 1528CGFLGALWKALSELLKNLIDWWNGSEQ ID NO: 1529CFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1530CGFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1531CGLFGELEGFIENGLKNLIDWWNGSEQ ID NO: 1532CGLFGELEGLLWHGLKNLIDWWNGSEQ ID NO: 1533CGLFGELAELLWHGLKNLIDWWNGSEQ ID NO: 1534CGLFGELAELLWQGLKNLIDWWNGSEQ ID NO: 1535CGLFGELWELLWHGLKNLIDWWNGSEQ ID NO: 1536CGLFGELWELLWQGLKNLIDWWNGSEQ ID NO: 1537CGLFEELAGLLWHGLKNLIDWWNGSEQ ID NO: 1538CGLFEELWGLLWHGLKNLIDWWNGSEQ ID NO: 1539CGLFEELAGLLWQGLKNLIDWWNGSEQ ID NO: 1540CGLFEELWGLLWQGLKNLIDWWNGSEQ ID NO: 1541CGLFGELAELLWHGLKNLIDWWNKSEQ ID NO: 1542CGLFEELAELLWHGLKNLIDWWNKSEQ ID NO: 1543CGLFGELAELLWHGLKNLIDWWHSEQ ID NO: 1544CGLFEELAELLWHGLKNLIDWWNHSEQ ID NO: 1545CGLFAELWGLLWQGLKNLIDWWNGSEQ ID NO: 1546CGLFAELWGLLWHGLKNLIDWWNGSEQ ID NO: 1547CGLFAELWGLLWHGLHNLLDWWNGSEQ ID NO: 1548CGLFAELAELLWEGLKNLIDWWNGSEQ ID NO: 1549CGLFAELAELLWHGLKNLIDWWNGSEQ ID NO: 1550CGLFAELELLWQGLKNLIDWWNGSEQ ID NO: 1551CELFGELAGLLWHGLKNLIDWWNGSEQ ID NO: 1552CLFEALWE-Aib-LEKLFSEQ ID NO: 1553CFLEALWELLEHLLSEQ ID NO: 1554CFLEALWKALEKLLSEQ ID NO: 1555CGLF-Aib-EIAGLLEEGLHNLIDWWNGSEQ ID NO: 1556CGLFGEI-Aib-GLLEEGLHNLIDWWNGSEQ ID NO: 1557CGFFGEIAGLLEE-Aib-LHNLIDWWNGSEQ ID NO: 1558CGLFGEIAGLLEEGLHNLIDWWN-AibSEQ ID NO: 1559CGLF-Aib-EIAGLLEE-Aib-LHNLIDWWNGSEQ ID NO: 1560CGFFGEI-Aib-GLLEE-Aib-LHNLIDWWNGSEQ ID NO: 1561CGFFGEI-Aib-ELIWEGLKNLIDWWNGSEQ ID NO: 1562CGFFGEIAELIWELKNLIDWWN-AibSEQ ID NO: 1563CGFF Aib-EIAELIWE-Aib-LKNLIDWWNGSEQ ID NO: 1564AC-CFLGALWKALSHLLSEQ ID NO: 1565AC-CFLEELWELLEELLESEQ ID NO: 1566AC-CLFGALWKALSELLSEQ ID NO: 1567AC-CGIGAVLKVLTTGLPALISWIKRKRQQSEQ ID NO: 1568AC-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 1569AC-CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl)SEQ ID NO: 1570Ac-CFLGALWKALSHLLSEQ ID NO: 1571Ac-CFLGALWKALSELLSEQ ID NO: 1572CELFEEIAELLWEGLENLIDWWNGSEQ ID NO: 1573CGLFGEIAELIWEGLENLIDWWNGSEQ ID NO: 1574CGLFGEIEELLEEGLENLIDWWNGSEQ ID NO: 1575CGLFAELAELLWEGLENLIDWWNGSEQ ID NO: 1576CGLFAELAELLEEGLENLIDWWNGSEQ ID NO: 1577CGLFAELAELLWEGLENLIDWWNSSEQ ID NO: 1578CGLFAELAELLEEGLENLIDWWNSSEQ ID NO: 1579CGLFAELAELLWEGLENLIDWWNQSEQ ID NO: 1580CGLFAELAELLEEGLENLIDWWNQSEQ ID NO: 1581CGLFAELAELLWEGLENLIDWWNESEQ ID NO: 1582CGLFAELAELLEEGLENLIDWWNESEQ ID NO: 1583CELFEELAELLWEGLENLIDWWNQSEQ ID NO: 1584CELFEELAELLWEGLENLIDWWNESEQ ID NO: 1585CELFEELAELLEEGLENLIDWWNGSEQ ID NO: 1586CELFAELAELLWEGLENLIDWWNGSEQ ID NO: 1587CELFAELAELLEEGLENLIDWWNGSEQ ID NO: 1588CELFAELAELLWEGLENLIDWWNSSEQ ID NO: 1589CELFAELAELLEEGLENLIDWWNSSEQ ID NO: 1590CELFAELAELLWEGLENLIDWWNQSEQ ID NO: 1591CELFAELAELLEEGLENLIDWWNQSEQ ID NO: 1592CELFAELAELLWEGLENLIDWWNESEQ ID NO: 1593CELFAELAELLEEGLENLIDWWNESEQ ID NO: 1594CELFEELAELLWEGLHNLIDWWNGSEQ ID NO: 1595CELFEELAELLWEGLHNLIDWWNSSEQ ID NO: 1596CELFEELAELLWEGLHNLIDWWNQSEQ ID NO: 1597CELFEELAELLWEGLHNLIDWWNESEQ ID NO: 1598CELFGELEGFIENGLENLIDWWNGSEQ ID NO: 1599CGLFEELEGFIENGLENLIDWWNGSEQ ID NO: 1600CGLFAELAGFIENGLENLIDWWNGSEQ ID NO: 1601CGLFAELEGFIENGLENLIDWWNGSEQ ID NO: 1602CGLFGELAGFIENGLENLIDWWNGSEQ ID NO: 1603CELFEELEGFIENGLENLIDWWNGSEQ ID NO: 1604CELFAELAGFIENGLENLIDWWNGSEQ ID NO: 1605CGLFGELEGFIWNGLENLIDWWNGSEQ ID NO: 1606CGLFGELEGFIENGLENLIDWWNGSEQ ID NO: 1607CGLFGELEGFIENGLENLIDWWNQSEQ ID NO: 1608CGLFGELEGFIENGLENLIDWWNESEQ ID NO: 1609CELFEELEGFIENGLENLIDWWNESEQ ID NO: 1610CGLLEEIAELLEEGLENLIDWWNSSEQ ID NO: 1611CGLLEEIEELLWEGLENLIDWWNSSEQ ID NO: 1612CELLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1613CGLLEEIAELLWEGLENLIDWWNSSEQ ID NO: 1614CELLEEIAELLWEGLENLIDWWNSSEQ ID NO: 1615CELLEEIEELLEEGLENLIDWWNESEQ ID NO: 1616CGLLEELEELLEEGLENLIDWWNSSEQ ID NO: 1617CGLLEELEELLEEGLENLLEWWNSSEQ ID NO: 1618CGLLEEIAELLEEGLENLIDWWNGSEQ ID NO: 1619CGLLAEIAELLEEGLENLIDWWNSSEQ ID NO: 1620CGLLAEIAELLWEGLENLIDWWNSSEQ ID NO: 1621CGLLEEIEGFIENGLENLIDWWNSSEQ ID NO: 1622CGLLEEIEGFIENGLENLIDWWNGSEQ ID NO: 1623CGLLEEIEELLEEGLE-Cit-LIDWWNSSEQ ID NO: 1624CGLLEEIEELLEQGLENLIDWWNSSEQ ID NO: 1625CGLLAELAELLEEGLENLIDWWNSSEQ ID NO: 1626CGLLEEIEELLEEGLENLIDWWNASEQ ID NO: 1627CGLL-Aib-EIEELLEEGLENLIDWWNSSEQ ID NO: 1628CGLLEEIEELLEEGLENLIDWWN-AibSEQ ID NO: 1629CGLLEEIEELLEE-Aib-LENLIDWWNGSEQ ID NO: 1630CGLFGHIHHLIHHGLHNLIDWWNGSEQ ID NO: 1631CGLFGEIHHLIHHGLHNLIDWWNGSEQ ID NO: 1632CGLFGEIHHLIHHGLENLIDWWNGSEQ ID NO: 1633CGLFGEIHELIHHGLENLIDWWNGSEQ ID NO: 1634CELLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1635CGLFGELEELIEEGLENLIDWWNGSEQ ID NO: 1636CGLLAEIEELLWEGLENLIDWWNSSEQ ID NO: 1637CGLLEEIEELLEEGLENLLEWWNSSEQ ID NO: 1638C(b-ALA)LLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1639CGLLEEIEELLEEGLENLIDLWNSSEQ ID NO: 1640CGLLEEIEELLEWGLENLIDWWNSSEQ ID NO: 1641CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1642CGFFGEIAELIEEGLKNLIDWGNGSEQ ID NO: 1643CGLFGEIEELIEEGLENLIDWANGSEQ ID NO: 1644CGLFGEIEELIEEGLENLIDWSNGSEQ ID NO: 1645CGLFGEIEELIEEGLENLIDW-(Aib)-NGSEQ ID NO: 1646CGLFGEIEELIEEGLENLIDWPNGSEQ ID NO: 1647CGLFGEIEELIEEGLENLIDWHNGSEQ ID NO: 1648CGLFGEIEELIEEGLENLIDWQNGSEQ ID NO: 1649CGLFGEIEELIEEGLENLIDWENGSEQ ID NO: 1650CGLFEEIAELIEEGLENLIDWGNGSEQ ID NO: 1651CELFEELAELLWEGLENLIDWGNSSEQ ID NO: 1652CGLFGEIAELIWEGLENLIDWGNGSEQ ID NO: 1653CGLLEEIEELLEEGLENLIDWGNSSEQ ID NO: 1654CGLFAEIEELLEEGLENLIDWGNGSEQ ID NO: 1655CGLL-(Aib)-EIEELLEEGLENLIDWWNSSEQ ID NO: 1656CGLFGEIEELIEEGLENLIDWNNGSEQ ID NO: 1657CGLFGEIEELIEEGLENLIDWDNGSEQ ID NO: 1658CGLFGEIEELIEEGLENLIDWONGSEQ ID NO: 1659CGLFAEIEELLEEGLENLIDWGNGSEQ ID NO: 1660CGLL-Aib-EIEELLEEGLENLIDWGNSSEQ ID NO: 1661CGLFGEIEELIEEGLENLIDGWNGSEQ ID NO: 1662CGLFGEIEELIEEGLENLIDLWNGSEQ ID NO: 1663CGWFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1664CGLFGEVEELIEEGLENLIDWWNGSEQ ID NO: 1665CGLFGEIEEVIEEGLENLIDWWNGSEQ ID NO: 1666CGLFGEIEELVEEGLENLIDWWNGSEQ ID NO: 1667CGLFGEIEELAEEGLENLIDWWNGSEQ ID NO: 1668CGLFGEIEELIDEGLENLIDWWNGSEQ ID NO: 1669CGLFGEIEELIEDGLENLIDWWNGSEQ ID NO: 1670CGLFGEIEELIEEGLEALIDWWNGSEQ ID NO: 1671CGLFGEIEELIEEGLENIIDWWNGSEQ ID NO: 1672CGLFGEIEELIEEGLEN-(Nle)-lDWWNGSEQ ID NO: 1673CGLFGEIEELIEEGLENLIGWWNGSEQ ID NO: 1674CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRR all (D)SEQ ID NO: 1675CGLFEAIEGFIENGWEGMIDGWYG all (D)SEQ ID NO: 1676CGLFGEIEELIENGLKNLIDWWYGYGRKKRRQRR all (D)SEQ ID NO: 1677CGLFEALLELLESLWELLLEAYGRKKRRQRR all (D)SEQ ID NO: 1678CGLFEEIEGFIENGWEGLIDWWYGYGHKKHHQHR all (D)SEQ ID NO: 1679CGLFGEIEELIEEGLENLIDWWNE all (D)SEQ ID NO: 1680CGLFGEIEELIEEGLENLIDWWNS all (D)SEQ ID NO: 1681CGLFGEIEELIEEGLENLIDWWNQ all (D)SEQ ID NO: 1682CYGRKKRRQRRLIRLWSHLIHIWFQNRRLKWKKKSEQ ID NO: 1683CGLFEAIEEFIENGWEGMIDGWYGYGRKKRRQRRSEQ ID NO: 1684CGLFFAIEGFIENGWEGMIDWWYGYGRKKRRQRR ALL (D)SEQ ID NO: 1685CGLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRK(STEARYL) ALL (D)SEQ ID NO: 1686(STEARYL)GLFELIEGFIENGWEGMIDGWYGYGRKKRRQRRC ALL (D)SEQ ID NO: 1687CFFGAIWEFIKSILK(STEARYL) +C-TERM K(STEARYL) ALL(D)SEQ ID NO: 1688CFFGAIWEFIKSILK(STEARYL) +C-TERM K(STEARYL) ALL(D)SEQ ID NO: 1689LAURYL-FFGAIWEFIKSILC ALL (D)SEQ ID NO: 1690CFFGAIWEFIHSILK(STEARYL) ALL (D)SEQ ID NO: 1691CGFFGEIAELIEEGLKNLIDWWNG ALL (D)SEQ ID NO: 1692CGIFEAIAGLLKNIFKGIFEAIAGLLKNIFK ALL (D)SEQ ID NO: 1693CIFGAIAGFIKNILKGLIDG ALL (D)SEQ ID NO: 1694CGLFEAIEGFIENGWEGMIDGWYGYGRKKRRQRRK(stearyl) all(D)SEQ ID NO: 1695(LAURYL)FFGAIWEFIKSILC all (D)SEQ ID NO: 1696CGLFGEIEELIEEGLENLIDWDNGSEQ ID NO: 1696glfgeieeliecglenlidwgngSEQ ID NO: 1697glfgeieelieeclenlidwgngSEQ ID NO: 1698cglfgeeleelleeglenlidgSEQ ID NO: 1699cglfgeeleelleeglenliegSEQ ID NO: 1700CGLFGEIEELIEEGLENLIDW-Aib-NGSEQ ID NO: 1701AC-GLLEEIEELLEEGLENLIDWWNSCSEQ ID NO: 1702GLLEEIEELLEEGLENLAELAEALEALAAGGSCSEQ ID NO: 1703CGLFGEIEELIEEGLENLIDWSEQ ID NO: 1704CGLFGEIEELIEEGLENLIDSEQ ID NO: 1705CGLFGEIEELIEEGLENLISEQ ID NO: 1706CELFEEIAELIEEGLENLIDWGSEQ ID NO: 1707AC-GLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1708AC-CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1709AC-CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1710CGFFGEI-AIB-GLLEE-AIB -LHNLIDWWNGSEQ ID NO: 1711CFLGALWKALSELLKNLIDWWNGSEQ ID NO: 1712CGL-R6H-GELEEL-S7H-EEGLENLIDWWNG (STAPLED)SEQ ID NO: 1713CGL-R6H-GELEEL-S7H-EEGLENLIDWWNG (STAPLED)SEQ ID NO: 1714CGFFGEI-AIB-ELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1715CGLFEELAGLLWHGLKNLIDWWNGSEQ ID NO: 1716CFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1717CGFF-AIB-EIAELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1718CGLFAEIEELIWEGLENLIDWWNQSEQ ID NO: 1719STEARYL-AGYLLGKLL-ORN-ORN-LAAAAL-ORN-ORN-LLCSEQ ID NO: 1720R-AHX-R-AHX-RILFQYR-AHX-B_ALA-R-AHX-R-B_ALA-CSEQ ID NO: 1721SEQ ID NO: 1722SEQ ID NO: 1723R-AHX-RR-AHX-RR-AHX-RIHILFQNRRMKWHK-B_ALA-CSEQ ID NO: 1724CSSAWWSYWPPVASEQ ID NO: 1725CGLFAVIKKVASVIGGLSEQ ID NO: 1726CGLFAVIHHVASVIGGLSEQ ID NO: 1727CGLFAVIEEVASVIGGLSEQ ID NO: 1728CGPSQPTYPGDDAPVRDLIRFYRDLRRYLNVVTRHRYSEQ ID NO: 1729CGIGAVLHVLTTGLPALISWIKRKRQQSEQ ID NO: 1730CGIGAVLHVLTTGLPALISWIHHHHQQSEQ ID NO: 1731AC-GIFEAIAGLLKINFKCSEQ ID NO: 1732AC-GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1733AC-GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1734AC-GIFEAIAGLLKINFKCSEQ ID NO: 1735AC-GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1736AC-GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1737GLFGEIEELIEEGLENLIDWGNGLAELAEALEALAAGGSCSEQ ID NO: 1738GLFGEIEELIEEGLENLIDWGNGLAELAEALEALAAGGSCSEQ ID NO: 1739GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1740GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1741GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1742GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1743CEENWIGLFGGGNIWEEEEILDLLSEQ ID NO: 1744CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1745CEALFGKINAIFIGKLSEQ ID NO: 1746CGLFGEIEELLEEGLENLIDWGNGSEQ ID NO: 1747CGLFGEIEELIEEALENLIDWGNGSEQ ID NO: 1748CGLFGEIEELIEEGFENLIDWGNGSEQ ID NO: 1749CGLFGEIEELIEEGFENLIDWGNGSEQ ID NO: 1750CGLFGEIEELIEEGWENLIDWGNGSEQ ID NO: 1751CGLFGEIEEWIEEGLENLIDWGNGSEQ ID NO: 1752CGLFGEIEEFIEEGLENLIDWGNGSEQ ID NO: 1753CGLFGEIEEFIEEGLENLIDWGNGSEQ ID NO: 1754CGLFGEIEELFEEGLENLIDWGNGSEQ ID NO: 1755CGLFGEIEELIEEGLENLIDWGNESEQ ID NO: 1756CGLFGEIEELIEEGLENLIDWGNESEQ ID NO: 1757CGLFGEIEELIEEGLEELIDWGNGSEQ ID NO: 1758CGLFGEIEELIEEGLESLIDWGNGSEQ ID NO: 1759CGLFGEIEELIEEGLEQLIDWGNGSEQ ID NO: 1760CGLFGEIEELIEEGLENWIDWGNGSEQ ID NO: 1761CGLFGEIEELIEEGLENFIDWGNGSEQ ID NO: 1762CGLFGEIEELIEEGLENLWDWGNGSEQ ID NO: 1763CGLFGEIEELIEEGLENLVDWGNGSEQ ID NO: 1764CGLFGEIEELIEEGLENLIEWGNGSEQ ID NO: 1765CGLFGEIEELIEEGLENLIDFGNGSEQ ID NO: 1766CGLFGEIEELIEEGLENLIDLGNGSEQ ID NO: 1767CGLFGEIEELIEEGLENLIDWGYGSEQ ID NO: 1768CGLFGEIEELIEEGLENLIDWGSGSEQ ID NO: 1769CGLFGEIEELIEEGLENLIDWGNQSEQ ID NO: 1770CGLFGEIEELIEEGLENLIDWGN-AIBSEQ ID NO: 1771CGLFEALLELLESLWELLLEAGYGSEQ ID NO: 1772CGLFGEIEELIEEGLENLIDWGNSSEQ ID NO: 1746CGLFEAIEGFIENGWEGMIDWGNGSEQ ID NO: 1773CIFGIDDLEEGLLFVAIVEAGIGGYLLGSSEQ ID NO: 1774CGLFEALLELLESLWELLLEASEQ ID NO: 1775CGLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1776CGNFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1777CGLFAEIEELIEEGLENLIDWGNGSEQ ID NO: 1778CGLFEEIEELIEEGLENLIDWGNGSEQ ID NO: 1779CGLFGEIAELIEEGLENLIDWGNGSEQ ID NO: 1780CELFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1781CALFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1782C-AIB-LFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1783CGWFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1784CGLFGELEELIEEGLENLIDWGNGSEQ ID NO: 1785CGLFGEIEELWEEGLENLIDWGNGSEQ ID NO: 1786CGLFGEIEELWEEGLENLIDWGNGSEQ ID NO: 1787CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1788CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1789CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1790CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1791CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1792CGLLGEIEELIEEGLENLIDWGNGSEQ ID NO: 1793CGLFGAIEELIEEGLENLIDWGNGSEQ ID NO: 1794CGFFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1795CGLWGEIEELIEEGLENLIDWGNGSEQ ID NO: 1796CGLFGEWEELIEEGLENLIDWGNGSEQ ID NO: 1797CGLFGEFEELIEEGLENLIDWGNGSEQ ID NO: 1798CGLFGEIEELIEEGLENLLDWGNGSEQ ID NO: 1799CGLFGEIEELIEEGLENLIDWGQGSEQ ID NO: 1800GLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1801GFFGAIWEFIHSILSEQ ID NO: 1802

[0081] A subset of the peptides disclosed in Table 2 that can be used in the conjugates herein are listed in Table 2a. Table 2a. Suitable Peptide Sequences and IDPeptide SequenceSEQ ID NO:CIFGAIAGFIKNIWEGLISEQ ID NO: 26CFFGAIWEFIHSILSEQ ID NO: 74CGIFEAIAGLLKNIFKSEQ ID NO: 82CGIGAVLKVLTTGLPALISWIKRKRQQSEQ ID NO: 255CGFFGEIAELIEEGLKNLIDWWNGSEQ ID NO: 543CGFFGEIAELIWEGLKNLIDWWNGSEQ ID NO: 935CGLFGEIEELIEEGLENLIDWANGSEQ ID NO: 1078CFLEELWELLEHLLSEQ ID NO: 1248AC-CFLEELWELLEHLLSEQ ID NO: 1391CGLLEEIEELLEEGLENLIDWWNSSEQ ID NO: 1403CFLEELWGLLEHLLSEQ ID NO: 1419CLELWLEHLFLELESEQ ID NO: 1489CGLFAEIEELLEEGLENLIDWWNGSEQ ID NO: 1516CGLFGEIEELIEEGLE-CIT-LIDWWNGSEQ ID NO: 1517CGLFGEIEELIEEGLENLIDWWNESEQ ID NO: 1518CGLL-AIB-EIEELLEEGLENLIDWWNSSEQ ID NO: 1628CGLFGHIHHLIHHGLHNLIDWWNGSEQ ID NO: 1631CGLFGEIHHLIHHGLHNLIDWWNGSEQ ID NO: 1632CGLFGEIHHLIHHGLENLIDWWNGSEQ ID NO: 1633CGLFGEIHELIHHGLENLIDWWNGSEQ ID NO: 1634CGFFGEIAELIEEGLKNLIDWGNGSEQ ID NO: 1643CGLFGEIEELIEEGLENLIDWSNGSEQ ID NO: 1645CGLFGEIEELIEEGLENLIDWPNGSEQ ID NO: 1647CGLFGEIEELIEEGLENLIDWHNGSEQ ID NO: 1648CGLFGEIEELIEEGLENLIDWQNGSEQ ID NO: 1649CGLFGEIEELIEEGLENLIDWENGSEQ ID NO: 1650CGLFEEIAELIEEGLENLIDWGNGSEQ ID NO: 1651CELFEELAELLWEGLENLIDWGNSSEQ ID NO: 1652CGLFGEIAELIWEGLENLIDWGNGSEQ ID NO: 1653CGLLEEIEELLEEGLENLIDWGNSSEQ ID NO: 1654CGLFGEIEELIEEGLENLIDWNNGSEQ ID NO: 1657CGLFAEIEELLEEGLENLIDWGNGSEQ ID NO: 1660CGLFGEIEELIEEGLENLIDWONGSEQ ID NO: 1662CGLFGEIEELIEEGLENLIDWDNGSEQ ID NO: 1696GLFGEIEELIECGLENLIDWGNGSEQ ID NO: 1697CGLFGEIEELIEEGLENLIDW-AIB-NGSEQ ID NO: 1701AC-GLLEEIEELLEEGLENLIDWWNSCSEQ ID NO: 1702GLLEEIEELLEEGLENLAELAEALEALAAGGSCSEQ ID NO: 1703CGLFGEIEELIEEGLENLIDWSEQ ID NO: 1704CGLFGEIEELIEEGLENLIDSEQ ID NO: 1705CGLFGEIEELIEEGLENLISEQ ID NO: 1706CELFEEIAELIEEGLENLIDWGSEQ ID NO: 1707AC-GLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1708AC-CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1709AC-CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1710CGFFGEI-AIB-GLLEE-AIB-LHNLIDWWNGSEQ ID NO: 1711CFLGALWKALSELLKNLIDWWNGSEQ ID NO: 1712CGL-R6H-GELEEL-S7H-EEGLENLIDWWNG (STAPLED)SEQ ID NO: 1713CGFFGEI-AIB-ELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1715CGLFEELAGLLWHGLKNLIDWWNGSEQ ID NO: 1716CFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1717CGFF-AIB-EIAELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1718CGLFAEIEELIWEGLENLIDWWNQSEQ ID NO: 1719STEARYL-AGYLLGKLL-ORN-ORN-LAAAAL-ORN-ORN-LLCSEQ ID NO: 1720R-AHX-R-AHX-RILFQYR-AHX-B_ALA-R-AHX-R-B_ALA-CSEQ ID NO: 1721SEQ ID NO: 1722SEQ ID NO: 1723R-AHX-RR-AHX-RR-AHX-RIHILFQNRRMKWHK-B_ALA-CSEQ ID NO: 1724CSSAWWSYWPPVASEQ ID NO: 1725CGLFAVIKKVASVIGGLSEQ ID NO: 1726CGLFAVIHHVASVIGGLSEQ ID NO: 1727CGLFAVIEEVASVIGGLSEQ ID NO: 1728CGPSQPTYPGDDAPVRDLIRFYRDLRRYLNVVTRHRYSEQ ID NO: 1729CGIGAVLHVLTTGLPALISWIKRKRQQSEQ ID NO: 1730CGIGAVLHVLTTGLPALISWIHHHHQQSEQ ID NO: 1731AC-GIFEAIAGLLKINFKCSEQ ID NO: 1732AC-GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1733AC-GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1734GLFGEIEELIEEGLENLIDWGNGLAELAEALEALAAGGSCSEQ ID NO: 1738GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1740GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1741CEENWIGLFGGGNIWEEEEILDLLSEQ ID NO: 1744CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1745CEALFGKINAIFIGKLSEQ ID NO: 1746CGLFGEIEELLEEGLENLIDWGNGSEQ ID NO: 1747CGLFGEIEELIEEALENLIDWGNGSEQ ID NO: 1748CGLFGEIEELIEEGFENLIDWGNGSEQ ID NO: 1749CGLFGEIEELIEEGWENLIDWGNGSEQ ID NO: 1751CGLFGEIEEWIEEGLENLIDWGNGSEQ ID NO: 1752CGLFGEIEEFIEEGLENLIDWGNGSEQ ID NO: 1753CGLFGEIEELFEEGLENLIDWGNGSEQ ID NO: 1755CGLFGEIEELIEEGLENLIDWGNESEQ ID NO: 1756CGLFGEIEELIEEGLEELIDWGNGSEQ ID NO: 1758CGLFGEIEELIEEGLESLIDWGNGSEQ ID NO: 1759CGLFGEIEELIEEGLEQLIDWGNGSEQ ID NO: 1760CGLFGEIEELIEEGLENWIDWGNGSEQ ID NO: 1761CGLFGEIEELIEEGLENFIDWGNGSEQ ID NO: 1762CGLFGEIEELIEEGLENLWDWGNGSEQ ID NO: 1763CGLFGEIEELIEEGLENLVDWGNGSEQ ID NO: 1764CGLFGEIEELIEEGLENLIEWGNGSEQ ID NO: 1765CGLFGEIEELIEEGLENLIDFGNGSEQ ID NO: 1766CGLFGEIEELIEEGLENLIDLGNGSEQ ID NO: 1767CGLFGEIEELIEEGLENLIDWGYGSEQ ID NO: 1768CGLFGEIEELIEEGLENLIDWGSGSEQ ID NO: 1769CGLFGEIEELIEEGLENLIDWGNQSEQ ID NO: 1770CGLFGEIEELIEEGLENLIDWGN-AIBSEQ ID NO: 1771CGLFEALLELLESLWELLLEAGYGSEQ ID NO: 1772CGLFEAIEGFIENGWEGMIDWGNGSEQ ID NO: 1773CIFGIDDLEEGLLFVAIVEAGIGGYLLGSSEQ ID NO: 1774CGLFEALLELLESLWELLLEASEQ ID NO: 1775CGLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1776CGNFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1777CGLFAEIEELIEEGLENLIDWGNGSEQ ID NO: 1778CGLFEEIEELIEEGLENLIDWGNGSEQ ID NO: 1779CGLFGEIAELIEEGLENLIDWGNGSEQ ID NO: 1780CELFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1781CALFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1782C-AIB-LFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1783CGWFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1784CGLFGELEELIEEGLENLIDWGNGSEQ ID NO: 1785CGLFGEIEELWEEGLENLIDWGNGSEQ ID NO: 1786CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1788CGLLGEIEELIEEGLENLIDWGNGSEQ ID NO: 1793CGLFGAIEELIEEGLENLIDWGNGSEQ ID NO: 1794CGFFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1795CGLWGEIEELIEEGLENLIDWGNGSEQ ID NO: 1796CGLFGEWEELIEEGLENLIDWGNGSEQ ID NO: 1797CGLFGEFEELIEEGLENLIDWGNGSEQ ID NO: 1798CGLFGEIEELIEEGLENLLDWGNGSEQ ID NO: 1799CGLFGEIEELIEEGLENLIDWGQGSEQ ID NO: 1800GLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1801GFFGAIWEFIHSILSEQ ID NO: 1802

[0082] A subset of the peptides disclosed in table 2 that can be used in the conjugates herein are listed in Table 2b. Table 2b. Suitable Peptide Sequences and IDPeptide SequenceSEQ ID NO:GLFGEIEELIECGLENLIDWGNGSEQ ID NO: 1697CGLFGEIEELIEEGLENLIDW-AIB-NGSEQ ID NO: 1701AC-GLLEEIEELLEEGLENLIDWWNSCSEQ ID NO: 1702GLLEEIEELLEEGLENLAELAEALEALAAGGSCSEQ ID NO: 1703CGLFGEIEELIEEGLENLIDWSEQ ID NO: 1704CGLFGEIEELIEEGLENLIDSEQ ID NO: 1705CGLFGEIEELIEEGLENLISEQ ID NO: 1706CELFEEIAELIEEGLENLIDWGSEQ ID NO: 1707AC-GLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1708AC-CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1709AC-CGLFGEIEELIEEGLENLIDWWNGSEQ ID NO: 1710CGFFGEI-AIB-GLLEE-AIB -LHNLIDWWNGSEQ ID NO: 1711CFLGALWKALSELLKNLIDWWNGSEQ ID NO: 1712CGL-R6H-GELEEL-S7H-EEGLENLIDWWNG (STAPLED)SEQ ID NO: 1713CGFFGEI-AIB-ELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1715CGLFEELAGLLWHGLKNLIDWWNGSEQ ID NO: 1716CFLGALFHALSHLLENLIDWWNGSEQ ID NO: 1717CGFF-AIB-EIAELIWE-AIB-LKNLIDWWNGSEQ ID NO: 1718CGLFAEIEELIWEGLENLIDWWNQSEQ ID NO: 1719STEARYL-AGYLLGKLL-ORN-ORN-LAAAAL-ORN-ORN-LLCSEQ ID NO: 1720R-AHX-R-AHX-RILFQYR-AHX-B_ALA-R-AHX-R-B ALA-CSEQ ID NO: 1721SEQ ID NO: 1722SEQ ID NO: 1723R-AHX-RR-AHX-RR-AHX-RIHILFQNRRMKWHK-B_ALA-CSEQ ID NO: 1724CSSAWWSYWPPVASEQ ID NO: 1725CGLFAVIKKVASVIGGLSEQ ID NO: 1726CGLFAVIHHVASVIGGLSEQ ID NO: 1727CGLFAVIEEVASVIGGLSEQ ID NO: 1728CGPSQPTYPGDDAPVRDLIRFYRDLRRYLNVVTRHRYSEQ ID NO: 1729CGIGAVLHVLTTGLPALISWIKRKRQQSEQ ID NO: 1730CGIGAVLHVLTTGLPALISWIHHHHQQSEQ ID NO: 1731AC-GIFEAIAGLLKINFKCSEQ ID NO: 1732AC-GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1733AC-GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1734GLFGEIEELIEEGLENLIDWGNGLAELAEALEALAAGGSCSEQ ID NO: 1738GLFEAIEGFIENGWEGLAELAEALEALAAGGSCSEQ ID NO: 1740GLFGALAEALAEALAEHLAEALAEALEALAAGGSCSEQ ID NO: 1741CEENWIGLFGGGNIWEEEEILDLLSEQ ID NO: 1744CGLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1745CEALFGKINAIFIGKLSEQ ID NO: 1746CGLFGEIEELLEEGLENLIDWGNGSEQ ID NO: 1747CGLFGEIEELIEEALENLIDWGNGSEQ ID NO: 1748CGLFGEIEELIEEGFENLIDWGNGSEQ ID NO: 1749CGLFGEIEELIEEGWENLIDWGNGSEQ ID NO: 1751CGLFGEIEEWIEEGLENLIDWGNGSEQ ID NO: 1752CGLFGEIEEFIEEGLENLIDWGNGSEQ ID NO: 1753CGLFGEIEELFEEGLENLIDWGNGSEQ ID NO: 1755CGLFGEIEELIEEGLENLIDWGNESEQ ID NO: 1756CGLFGEIEELIEEGLEELIDWGNGSEQ ID NO: 1758CGLFGEIEELIEEGLESLIDWGNGSEQ ID NO: 1759CGLFGEIEELIEEGLEQLIDWGNGSEQ ID NO: 1760CGLFGEIEELIEEGLENWIDWGNGSEQ ID NO: 1761CGLFGEIEELIEEGLENFIDWGNGSEQ ID NO: 1762CGLFGEIEELIEEGLENLWDWGNGSEQ ID NO: 1763CGLFGEIEELIEEGLENLVDWGNGSEQ ID NO: 1764CGLFGEIEELIEEGLENLIEWGNGSEQ ID NO: 1765CGLFGEIEELIEEGLENLIDFGNGSEQ ID NO: 1766CGLFGEIEELIEEGLENLIDLGNGSEQ ID NO: 1767CGLFGEIEELIEEGLENLIDWGYGSEQ ID NO: 1768CGLFGEIEELIEEGLENLIDWGSGSEQ ID NO: 1769CGLFGEIEELIEEGLENLIDWGNQSEQ ID NO: 1770CGLFGEIEELIEEGLENLIDWGN-AIBSEQ ID NO: 1771CGLFEALLELLESLWELLLEAGYGSEQ ID NO: 1772CGLFEAIEGFIENGWEGMIDWGNGSEQ ID NO: 1773CIFGIDDLEEGLLFVAIVEAGIGGYLLGSSEQ ID NO: 1774CGLFEALLELLESLWELLLEASEQ ID NO: 1775CGLFGEIEELIEEGLENLIDWGNGCSEQ ID NO: 1776CGNFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1777CGLFAEIEELIEEGLENLIDWGNGSEQ ID NO: 1778CGLFEEIEELIEEGLENLIDWGNGSEQ ID NO: 1779CGLFGEIAELIEEGLENLIDWGNGSEQ ID NO: 1780CELFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1781CALFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1782C-AIB-LFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1783CGWFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1784CGLFGELEELIEEGLENLIDWGNGSEQ ID NO: 1785CGLFGEIEELWEEGLENLIDWGNGSEQ ID NO: 1786CGLFGEIEELIEE-AIB-LENLIDWGNGSEQ ID NO: 1788CGLLGEIEELIEEGLENLIDWGNGSEQ ID NO: 1793CGLFGAIEELIEEGLENLIDWGNGSEQ ID NO: 1794CGFFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1795CGLWGEIEELIEEGLENLIDWGNGSEQ ID NO: 1796CGLFGEWEELIEEGLENLIDWGNGSEQ ID NO: 1797CGLFGEFEELIEEGLENLIDWGNGSEQ ID NO: 1798CGLFGEIEELIEEGLENLLDWGNGSEQ ID NO: 1799CGLFGEIEELIEEGLENLIDWGQGSEQ ID NO: 1800GLFGEIEELIEEGLENLIDWGNGSEQ ID NO: 1801GFFGAIWEFIHSILSEQ ID NO: 1802 Linkers

[0083] The attachment between a ligand G and an oligonucleotide and / or between a ligand G and a peptide may be mediated by a linker. This linker may be cleavable or non-cleavable, depending on the application. In certain embodiments, a cleavable linker may be used to release the oligonucleotide after transport from the endosome to the cytoplasm. The intended nature of the conjugation or coupling interaction, or the desired biological effect, will determine the choice of linker group. Linker groups may be combined or branched to provide more complex architectures. Suitable linkers include those as described in WO2009 / 126933.

[0084] In one embodiment, a suitable linker is selected from Table 3: Table 3. Suitable Linkers R' = H, Boc, Cbz, Ac, PEG, lipid, targeting ligand, linker(s) and / or peptide(s) wherein p is 1 to 10 wherein m is 0 to 10 where "LG" is a linker selected from the group consisting of: Note: n = 0- 750

[0085] In one embodiment, a suitable linker is selected from Table 3a: Table 3a. Suitable Linkers R' = H, Boc, Cbz, Ac, PEG, lipid, targeting ligand, linker(s) and / or peptide(s) wherein m is 1 to 6.Note: n = 0 - 750.

[0086] Commercial linkers are available from various suppliers such as Pierce or Quanta Biodesign including combinations of said linkers. The linkers may also be combined to produce more complex branched architectures accomodating from 1 to 6 targeting ligands and / or 1 to 6 peptides. In one embodiment, a combined targeting ligands and linkers has the structure T-L-1 as shown below: Targeting Ligands

[0087] The compositions and peptide conjugates of the present invention may comprise a targeting ligand. The term "targeting ligand" as used herein refers to its meaning as is generally accepted in the art. The term generally refers to a moiety that confers some degree of target specificity to one or more cells, tissues, or organs, such as in a subject or organism and thus the ability to target such cells, tissues, or organs with a compound or composition of interest.

[0088] In some embodiments, this targeting ligand may direct the modular composition to a particular cell. For example, the targeting ligand may specifically or non-specifically bind with a molecule on the surface of a target cell. The targeting moiety can be a molecule with a specific affinity for a target cell. Targeting moieties can include antibodies directed against a protein found on the surface of a target cell, or the ligand or a receptor-binding portion of a ligand for a molecule found on the surface of a target cell. Examples and a further discription of targeting ligands can be found in WO2009 / 126933.

[0089] The targeting ligands are selected from the group consisting of an antibody, a ligand-binding portion of a receptor, a ligand for a receptor, an aptamer, D-galactose, N-acetyl-D-galactose (GalNAc), multivalent N-acytyl-D-galactose, D-mannose, cholesterol, a fatty acid, a lipoprotein, folate, thyrotropin, melanotropin, surfactant protein A, mucin, carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, multivalent mannose, multivalent fructose, glycosylated polyaminoacids, transferin, bisphosphonate, polyglutamate, polyaspartate, a lipophilic moiety that enhances plasma protein binding, a steroid, bile acid, vitamin B12, biotin, an RGD peptide, an RGD peptide mimic, ibuprofen, naproxen, aspirin, folate, and analogs and derivatives thereof.

[0090] In one embodiment, a targeting ligand is selected from the group consisting of D-galactose, N-acetyl-D-galactose (GalNAc), GalNAc2, and GalNAc3, cholesterol, folate, and analogs and derivatives thereof.

[0091] In one embodiment, each occurance of the targeting ligand G of the above compositions and peptide conjugates is independently selected from Table 4. Table 4. Suitable Ligands wherein each X is independently -O-, -S-, -CH 2 - or -NH-; and each n is independently 1, 2, 3, or 4, wherein each n is independently an integer from 1 to 20; wherein each n is independently an integer from 1 to 20; wherein n is an integer between 1 and 100, wherein n is an integer between 1 and 100. wherein n is an integer between 1 and 100.

[0092] In one embodiment, each occurance of G is independently selected from Table 4a. Table 4a. Suitable Ligands wherein each X is independently -O-, -S-, -CH 2 - or -NH-; and each n is independently 1, 2, 3, or 4.

[0093] In one embodiment, G of the above compositions and peptide conjugates comprises a ligand of the following formula: wherein each n is independently an integer from 1 to 20.

[0094] In another embodiment, G of the above compositions and peptide conjugates comprises a ligand of the following formula: wherein each n is independently an integer from 1 to 20.Lipids

[0095] In one embodiment, R-(L) a -(G) b further comprises a lipid, either directly or through a suitable linker L.

[0096] In another embodiment, the peptide containing conjugate (P) c -(L) d -(G) e further comprises a lipid either directly or through a suitable linker.

[0097] Lipids, such as cholesterol or fatty acids, when attached to highly hydrophilic molecules such as nucleic acids can substantially enhance plasma protein binding and consequently circulation half life. In addition, lipophilic groups can increase cellular uptake. For example, lipids can bind to certain plasma proteins, such as lipoproteins, which have consequently been shown to increase uptake in specific tissues expressing the corresponding lipoprotein receptors (e.g., LDL-receptor or the scavenger receptor SR-B1). Lipophilic conjugates can also be considered as a targeted delivery approach and their intracellular trafficking could potentially be further improved by the combination with endosomolytic agents.

[0098] Exemplary lipids that enhance plasma protein binding include, but are not limited to, sterols, cholesterol, fatty acids, cholic acid, lithocholic acid, dialkylglycerides, diacylglyceride, phospholipids, sphingolipids, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine, aspirin, naproxen, ibuprofen, vitamin E and biotin etc. Examples of lipids can be found in WO2009 / 126933.

[0099] In one embodiment, the lipid is cholesterol.Solubilizing Agents

[0100] The R-(L) a -(G) b composition and / or the peptide containing conjugate (P) c -(L) d -(G) e may further comprise one or more solubilizing agents that may enhance aqueous solubility, circulation half life and / or cellular uptake. These can include naturally occurring substances, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), high-density lipoprotein (HDL), or globulin); or a carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid). These moieties may also be a recombinant or synthetic molecule, such as a synthetic polymer or synthetic polyamino acids. Examples include polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG, e.g., PEG-0.5K, PEG-2K, PEG-5K, PEG-10K, PEG-12K, PEG-15K, PEG-20K, PEG-40K), methyl-PEG (mPEG), [mPEG]2,, polyvinyl alcohol (PVA), polyurethane, poly(2 ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Examples and a further discription of solubilizing agents can be found in WO2009 / 126933.

[0101] In one embodiment, the solubilizing group is PEG 0.5K to 30K.

[0102] In one embodiment, R-(L) a -(G) b comprises 1-4 targeting ligands. In another embodiment, R-(L) a -(G) b comprises 1-2 targeting ligands. In yet another embodiment, the composition comprises 1 targeting ligand.

[0103] In one embodiment, (P) c -(L) d -(G) e comprises 1-6 peptides. In another embodiment, (P) c -(L) d -(G) e comprises 1-4 peptides. In another embodiment, (P) c -(L) d -(G) e comprises 1-2 peptides. In yet another embodiment, (P) c -(L) d -(G) e comprises 1 peptide.

[0104] In one embodiment, the oligonucleotide is mRNA, and the ligand is attached to one or more terminal positions or through 2'-position of a nucleotide ribose ring.

[0105] In one embodiment, the oligonucleotide or siRNA is double stranded and there is one targeting ligand which is attached to the guide strand at a 2'-position of a nucleotide ribose ring, optionally through a suitable linker.

[0106] In one embodiment, the oligonucleotide or siRNA is double stranded and there is one targeting ligand which is attached to the guide strand at a terminal 3' or 5'-position, optionally through a suitable linker.

[0107] In one embodiment, the oligonucleotide or siRNA is double stranded and there is one targeting ligand which is attached to the passenger strand at a 2'-position of a nucleotide ribose ring, optionally through a suitable linker.

[0108] In one embodiment, the oligonucleotide or siRNA is double stranded and there is one targeting ligand which is attached to the passenger strand at a terminal 3' or 5'-position, optionally through a suitable linker.

[0109] In one embodiment, the oligonucleotide or siRNA is double stranded and two or more targeting ligands are attached to the guide strand at different 2'-positions of the ribose rings, optionally through a suitable linkers.

[0110] In one embodiment, the oligonucleotide or siRNA is double stranded and two or more targeting ligands are attached to two or more nucleotides of the guide strand, optionally through a suitable linkers, wherein the points of attachment are at different terminal 3' and / or 5'-positions.

[0111] In one embodiment, the oligonucleotide or siRNA is double stranded and two or more targeting ligands are attached to two or more nucleotides of the passenger strand, optionally through a suitable linkers, wherein the points of attachment are at different terminal 3' and / or 5'-positions.

[0112] In one embodiment, the oligonucleotide or siRNA is double stranded and two or more targeting ligands are attached to two or more nucleotides of both the guide strand and the passenger strand, optionally through a suitable linkers, wherein the points of attachment are at different terminal 3' and / or 5'-positions.

[0113] In one embodiment, the oligonucleotide or siRNA is double stranded and optional targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and / or masking agents are attached to the same or different strands via linkers. In one embodiment, each linker is independently selected Table 3. In another embodiment, each linker is independently selected Table 3a.

[0114] To illustrate the invention, the invention features a modular composition, comprising an oligonucleotide or siRNA (R), one or more targeting ligands (G), one or more peptides (P), one or more optional linkers (L), and one or more optional ligands (X), solubilizing groups (X), pharmacokinetics enhancing agents (X), lipids (X), and / or masking agents (X). In one embodiment, the oligonucleotide is an siRNA. In another embodiment, the oligonucleotide is mRNA.

[0115] In one embodiment, the oligonucleotide composition has the formula:         G-R.

[0116] In one embodiment, the oligonucleotide composition has the formula:         G-L-R.

[0117] In one embodiment, the oligonucleotide composition has the formula:         G-L-R-X.

[0118] In one embodiment, the oligonucleotide composition has the formula:         G-L-R-L-X.

[0119] In one embodiment, the oligonucleotide composition has the formula:         G-R-L-P

[0120] In one embodiment, the oligonucleotide composition has the formula:         G-L-R-L-P.

[0121] In one embodiment, the oligonucleotide composition has the formula:

[0122] In one embodiment, the oligonucleotide composition has the formula:

[0123] In one embodiment, a double stranded siRNA composition has the formula:         G-L-ds siRNA wherein the ds siRNA is a double stranded siRNA that comprises a passenger (sense) strand and a guide (antisense) strand, wherein the passenger strand nucleotide sequence is complimentary to the guide strand nucleotide sequence, and wherein the G-L- is attached to the 5' end of the passenger strand. In one embodiment of the composition, the G-L- is attached to the 3' end of the passenger strand. In one embodiment of the composition, the G-L- is attached to the 5' end of the guide strand. In one embodiment of the composition, the G-L- is attached to the 3' end of the guide strand.

[0124] When the oligonucleotide or siRNA is a double stranded oligonucleotide or siRNA, the "G-L-", "P-L-" and "X-L-" may be located on the same strand or on different strands.

[0125] In one embodiment, a double stranded siRNA composition has the formula:         G-L-ds siRNA-L-P, wherein the ds siRNA is a double stranded siRNA that comprises a passenger (sense) strand and a guide (antisense) strand, wherein the passenger strand nucleotide sequence is complimentary to the guide strand nucleotide sequence, wherein the G-L- is attached to the 5' end of the passenger strand, and wherein the P-L- is attached to the 3' end of the passenger strand. In one embodiment of the composition, the G-L- is attached to the 5' end of the passenger strand, and the P-L- is attached to the 5' end of the guide strand. In one embodiment of the composition, the G-L- is attached to the 3' end of the guide strand, and the P-L- is attached to the 5' end of the guide strand. In one embodiment of the composition, the G-L- is attached to the 3' end of the guide strand, and the P-L- is attached to the 3' end of the passenger strand.

[0126] In one embodiment, a double stranded siRNA composition has the formula: wherein the ds siRNA is a double stranded siRNA that comprises a passenger (sense) strand and a guide (antisense) strand, wherein the passenger strand nucleotide sequence is complimentary to the guide strand nucleotide sequence, wherein the G-L- is attached to the 5' end of the passenger strand, the P-L- is attached to the 3' end of the passenger strand, and the X-L- is attached to the 3' end of the guide strand. In one embodiment of the composition, the G-L- is attached to the 3' end of the guide strand, the P-L- is attached to the 3' end of the passenger strand, and the X-L- is attached to the 5' end of the passenger strand. In one embodiment of the composition, the G-L-is attached to the 3' end of the guide strand, the P-L- is attached to the 5' end of the guide strand, and the X-L- is attached to the 5' end of the passenger strand.

[0127] These examples are used as guidance. One skilled in the art will recognize that a variety of permutations for placing the desired components on the passenger and guide strand exist.

[0128] In some embodiments, when the oligonucleotide or siRNA is double-stranded and multiple "G-L", "P-L" and / or "X-L" components are present, such multiple "G-L", "P-L" and / or "X-L" components may all be present in one strand or both strands of the double stranded oligonucleotide or siRNA.

[0129] When multiple "G-L", "P-L" and / or "X-L" components are present, they may all be the same or different.

[0130] In some embodiments, the "G-L", "P-L" and "X-L" are on the same strand.

[0131] In some embodiments, the "G-L", "P-L" and "X-L" are on the passenger strand.

[0132] In some embodiments, the "G-L", "P-L" and "X-L" are on the guide strand.

[0133] In some embodiments, the "G-L", "P-L" and "X-L" are on different strands.

[0134] In some embodiments, the "G-L" is on the passenger strand and the "P-L" is on the guide strand.

[0135] In some embodiments, the "G-L" is on the guide strand and the "P-L" is on the passenger strand.

[0136] In some embodiments, the "G-L", "P-L" and "X-L" are on different strands but on the same terminal end of the double-stranded oligonucleotide or siRNA.

[0137] In some embodiments, the "G-L", "P-L" and "X-L" are on different strands and on the opposite terminal ends of the double-stranded oligonucleotide or siRNA.

[0138] In some embodiments, one or more "G-L", one or more "P-L" and / or one or more "X-L" of identical or different nature can be located on the guide strand or passenger starnd in the above embodiments.

[0139] In some embodiments, the "G-L" and "P-L" may be located on multiple terminal ends of either the passenger or guide strand and the "X-L" may be located on the remaining terminal ends of the passenger and guide strands.

[0140] The method can be performed in vitro, ex vivo or in vivo, e.g., to treat a subject identified as being in need of an oligonucleotide or siRNA. A subject in need of said oligonucleotide is a subject, e.g., a human, in need of having the expression of a gene or genes, e.g., a gene related to a disorder, downregulated or silenced.

[0141] In one aspect, the invention provides a method for inhibiting the expression of one or more genes. The method comprising contacting one or more cells with an effective amount of an oligonucleotide of the invention, wherein the effective amount is an amount that suppresses the expression of the one or more genes. The method can be performed in vitro, ex vivo or in vivo.

[0142] The methods and compositions of the invention can be used with any oligonucleotides or siRNAs known in the art. In addition, the methods and compositions of the invention can be used for the treatment of any disease or disorder known in the art, and for the treatment of any subject, e.g., any animal, any mammal, such as any human. One of ordinary skill in the art will also recognize that the methods and compositions of the invention may be used for the treatment of any disease that would benefit from downregulating or silencing a gene or genes.

[0143] One of ordinary skill in the art will further recognize that the methods and compositions of the invention may be used for expressing genes encoding proteins or polypeptides.

[0144] The methods and compositions of the invention may be used with any dosage and / or formulation described herein, or any dosage or formulation known in the art. In addition to the routes of administration described herein, a person skilled in the art will also appreciate that other routes of administration may be used to administer the modular composition of the invention.Method of Treatment

[0145] In one aspect, the invention features a method of treating a subject at risk for or afflicted with a disease that may benefit from the administration of the modular composition of the invention. The method comprises administering the modular composition of the invention to a subject in need thereof, thereby treating the subject. The oligonucleotide that is administered will depend on the disease being treated. See WO2009 / 126933 for additional details regarding methods of treatments for specific indications.Formulation

[0146] There are numerous methods for preparing conjugates of oligonucleotide and peptide compounds. The techniques should be familiar to those skilled in the art. A useful reference for such reactions is Bioconjugate Techniques, Hermanson, G. T., Academic Press, San Diego, CA, 1996. Other references include WO2005 / 041859; WO2008 / 036825 and WO2009 / 126933.

[0147] Unless otherwise noted, the following terminology and definitions apply as used in the present application.

[0148] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0149] Any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range, and when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0150] "About" or "approximately," as used herein, in reference to a number are generally taken to include numbers that fall within a range of 5% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Where ranges are stated, the endpoints are included within the range unless otherwise stated or otherwise evident from the context.

[0151] The phrase "biological system" as used herein refers to its meaning as is generally accepted in the art. The term generally refers to material, in a purified or unpurified form, from biological sources including, but not limited to, human or animal, wherein the system comprises the components required for RNAi activity. Thus, the phrase includes, for example, a cell, tissue, subject, or organism, or extract thereof. The term also includes reconstituted material from a biological source.

[0152] The term "cell" as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human being. The cell can be present in an organism, e.g., birds, plants and mammals, such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell). The cell can be of somatic or germ line origin, totipotent or pluripotent, dividing or non-dividing. The cell can also be derived from or can comprise a gamete or embryo, a stem cell, or a fully differentiated cell.

[0153] The terms "composition" or "formulation" as used herein refer to their generally accepted meaning in the art. These terms generally refer to a composition or formulation, such as in a pharmaceutically acceptable carrier or diluent, in a form suitable for administration, e.g., systemic or local administration, into a cell or subject, including, for example, a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, inhalation, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell. For example, compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms that prevent the composition or formulation from exerting its effect. As used herein, pharmaceutical formulations include formulations for human and veterinary use.

[0154] The term "including" (and any form thereof, such as "includes" and "include"), "comprising" (and any form thereof, such as "has" or "have") or "containing" (and any form thereof such as "contains" or "contain") are inclusive and open-ended and do not exclude additional, unrecited elements or method steps.

[0155] The terms "mammalian" or "mammal" as used herein refers to its meaning as is generally accepted in the art. The term generally refers to any warm blooded vertebrate species, such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0156] The term "subject" as used herein refers to its meaning as is generally accepted in the art. The term generally refers an organism to which the nucleic acid molecules of the invention can be administered. A subject can be a mammal or mammalian cells, including a human or human cells. The term also refers to an organism, which is a donor or recipient of explanted cells or the cells themselves.

[0157] The phrase "systemic administration" as used herein refers to its meaning as is generally accepted in the art. The phrase generally refers in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body.

[0158] The phrase "therapeutically effective amount" as used herein refers to its meaning as is generally accepted in the art. The term generally refers to the amount of the compound or composition that will elicit the biological or medical response of a cell, tissue, system, animal or human that is be sought by the researcher, veterinarian, medical doctor or other clinician. For example, if a given clinical treatment is considered effective when there is at least a 25% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is that amount necessary to effect at least a 25% reduction in that parameter.EXAMPLES

[0159] The invention is further illustrated by the following examples, which should not be construed as further limiting. The siRNAs described herein were designed to target CTNNB1 (Beta Catenin).Preparations of Compounds A9 and A10

[0160] TetraGalNAc Compounds A9 and A10 were prepared using steps and conditions as described in Scheme 1. Synthesis of (2S)-2, 6-bis[bis (prop-2-yn-1-yl)amino]hexanoic acid (Compound A1)

[0161] Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (2S)-2,6-diaminohexanoic acid (50 g, 342.03 mmol, 1.00 equiv) in acetonitrile (1000 mL) and heated to 50°C. To this was added potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv, 85%). The resulting solution was stirred for 30 min. Then 3-bromoprop-1-yne (29.5 mL, 1.00 equiv) was added. The resulting solution was stirred for 1 hour at 50°C. Additional potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv) was added to the solution and stirred for 30 min at 50°C. To this was added 3-bromoprop-1-yne (29.5 mL, 1.00 equiv). The resulting solution was stirred for 1 hour. To this was added potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv) again. The resulting solution was stirred for 30 min at 50°C, followed by addition of more 3-bromoprop-1-yne (29.5 mL, 1.00 equiv). The resulting solution was stirred for 1 hour. To this was added potassium hydroxide (22.6 g, 0.4025 mol, 1.00 equiv). The resulting solution was stirred for 30 min. To this was added 3-bromoprop-1-yne (29.5 mL, 1.00 equiv). The resulting solution was stirred for 3 hours. The reaction mixture was cooled to 25°C with a water / ice bath. The solid was filtered out. The filtrate was adjusted to pH 4 with HCl (6M). The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane / methanol (100:1-25:1). This resulted in Compound A1 as an oil. MS(ES, m / z): 297.2, [M-H] - 1< HNMR(CDCl 3 , 500MHz, ppm): 3.62 (d, J = 2.0 Hz, 4H), 3.52-3.49 (m, 1H), 3.50 (d, J = 2.4 Hz, 4H), 2.62 (t, J = 7.1 Hz, 2H), 2.30 (t, J = 2.4 Hz, 2H), 2.27 (t, J = 2.4 Hz, 2H),1.88-1.79 (m, 2H), 1.60-1.53 (m, 2H), 1.52-1.43 (m, 2H).Synthesis of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Compound A3)

[0162] Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-hydroxyethoxy)ethan-1-ol (A2, 42.4 g, 399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirring for 1 h at 25°C, the resulting mixture was washed with 1x500 mL of aq. potassium hydrosulfate (1M) and 1x500 mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane / methanol (100:1). This resulted in Compound A3 as an oil.Synthesis of 2-(2-azidoethoxy)ethan-1-ol (Compound A4)

[0163] Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (A3, 50 g, 192.08 mmol, 1.00 equiv) in N,N-dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25°C. The resulting solution was stirred for 5 h at 100°C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane / methanol (80:1). This resulted in Compound A4 as an oil. 1< HNMR (CDCl 3 , 400 MHz, ppm): 3.42-3.45(t, J = 4.8Hz, 2H), 3.63-3.65(t, J = 4.8Hz, 2H), 3.71-3.74(t, J = 4.8Hz, 2H), 3.71-3.79(m, 2H).Synthesis of (3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (Compound A6)

[0164] Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol hydrochloride (A5, 120 g, 556.50 mmol, 1.00 equiv) in pyridine (1200 mL). This was followed by the addition of acetic anhydride (341.6 g, 3.35 mol, 6.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred overnight at 25°C. The reaction was then quenched by the addition of 8000 mL of water / ice. The solid was collected by filtration. This resulted in Compound A6 as a solid.Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (Compound A7)

[0165] Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (A6, 30 g, 77.05 mmol, 1.00 equiv) in dichloromethane (1500 mL), then added iron (III) chloride (30 g, 184.95 mmol, 2.40 equiv). The resulting mixture was stirred for 2 h at 25°C. The reaction was then quenched by the addition of 1000 mL of water / ice. The organic layer was washed with 1x1000 mL of sodium aq. bicarbonate and 1x1000 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in Compound A7 as an oil. 1< HNMR(CDCl 3 , 300MHz, ppm): 2.03(s, 9H), 2.12(s, 3H), 3.97-4.27(m, 4H), 4.90-4.93(m, J = 3.3Hz, 1H), 5.45-5.47(t, J= 3.0Hz, 1H), 5.98-6.00(d, J= 6.6Hz, 1H).Synthesis of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyl diacetate (Compound A8)

[0166] Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyl diacetate (A7, 40 g, 121.47 mmol, 1.00 equiv) in 1,2-dichloroethane (200 mL), 2-(2-azidoethoxy)ethan-1-ol (A4, 23.89 g, 182.18 mmol, 1.50 equiv). To the above several 4A zeolite was added. The resulting mixture was stirred for 1 h at 25°C. Then trimethylsilyl trifluoromethanesulfonate (10.8 mL, 0.50 equiv) was added. After stirred overnight at 25°C, the reaction mixture was diluted with 500 mL of dichloromethane and washed with 1x500 mL of water, 1x500 mL of aq. sodium bicarbonate and 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane / methanol (100:1). This resulted in Compound A8 as an oil. MS(m / z): 461.1, [M+H] +< 1< HNMR(CDCl 3 , 500MHz, ppm) 5.78 (d, J = 8.90 Hz, 1H), 5.36 (d, J = 2.9 Hz, 1H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.77 (d, J = 8.3 Hz, 1H), 4.19-4.12 (m, 2H), 4.11-4.05 (m, 1H), 3.98-3.92 (m, 2H), 3.82-3.78 (m, 1H), 3.71-3.63 (m, 4H), 3.49-3.38 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H).Synthesis of (S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoic acid (Compound A9, tetraGalNAc Acetate)

[0167] Into a 250-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged (2S)-2,6-bis [bis (prop-2-yn-1-yl) amino]hexanoic acid (A1, 1.0 g, 1.0 equiv), (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-azidoethoxy)ethoxy]tetrahydro-2H-pyran-3,4-diyl diacetate (A8, 9.26 g, 6.0 equiv), anhydrous THF 50 mL, CuBrSMe 2 (0.138 g, 0.20 equiv), and anhydrous DBU (1.5 ml, 3.0 equiv) in respective order. The resulting solution was stirred for 16 h at room temperature, quenched with acetic acid (0.75 mL, 4.0 equiv), treated with MP-TMT resin (Part No: 801472, from Biotage) (9 g), aged at room temperature for 16h, filtered, and concentrated the filtrate to a solid. The solid was then dissolved in CH 2 Cl 2 (140 mL), and washed with AcOH / NaCl solution (140 mL). The AcOH / NaCl solution was prepared with 1 mL AcOH and 100 mL 20% NaCl solution. The bottom organic layer was concentrated, and purified on a SiO 2 column (220 g), eluting with CH 2 Cl 2 / MeOH. This resulted in Compound A9 as a solid (tetraGalNAc Acetate). MS(m / z): 2139.5, [M+H] +< Synthesis of (S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoic acid (Compound A10, TetraGalNAc)

[0168] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged (S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoic acid (A9, 6.9 g, 1.0 equiv), Na 2 CO 3 (6.83 g, 20 eq), water (56 mL), and MeOH (32mL) in respective order. The reaction was aged at room temperature for 16h, concentrated to residue, redissolved in water (50mL), and purified on Combiflash C18 gold reverse column (415 g), eluting with water / MeCN. After concentration under vacuum, the product was dissolved in minimum amount of water, and lyophilized to obtain Compound A10 (tetraGalNAc) as a solid. MS(m / z): 1657 [M+Na] +< 1< HNMR(D 2 O, 500 MHz, ppm): 8.05 (s, 2H), 7.91 (s, 2H), 4.62 (t, J = 5.0 Hz, 4H), 4.57 (t, J = 5.0 Hz, 4H), 4.45-4.41 (d, J = 8.6 Hz, 4H), 3.99-3.82 (m, 28H), 3.80-3.61 (m, 28H), 3.14 (t, J = 7.1 Hz, 1H), 2.52 (broad s, 2H), 1.99 (s, 6H), 1.98 (s, 6H), 1.73 (m, 2H), 1.60 (m, 2H), 1.29 (m, 2H). Preparation of B2 to B4

[0169] Conjugates B2 to B4 were prepared using steps and conditions as described in Scheme 2. Synthesis of B2

[0170] HATU (30 mg, 0.080 mmol, 3 eq.) was dissolved in DMSO (400 uL) and added to a vial containing A10 (130 mg, 0.080 mmol, 3 eq.). The solution color turned pale yellow as the tetra GalNAc (A10) dissolved. DIEA (28 uL, 0.16 mmol, 6 eq.) was then added to the solution. Starting material passenger strand B1 (200 mg, 0.027 mmol, 1 eq.) was dissolved in water (400 uL) and diluted with DMSO (800 uL). The HATU solution was added to the RNA solution and mixed thoroughly. The reaction mixture was left at room temperature for 20 minutes. The reaction mixture was diluted with water to bring the total DMSO content to 5% and centrifugal dialyzed two times against water over a 3K membrane. Expected mass: 9147.5, found mass: 9149.0Synthesis of B4

[0171] Guide strand (B3, 58 mg) was dissolved in water (5 mL) and added to a vial containing B2 (79 mg). The solution was thoroughly mixed and left at room temperature for 2 hours. The solution was freeze dried to afford the duplex as a solid.Synthesis of Compounds C1 and C2

[0172] Compounds C1 to C2 were prepared using steps and conditions as described in Scheme 3. Synthesis of N,N'-((2S,2'S,3S,3'S,4S,4'S,5S,5'S,6S,6'S)-2,2'-(((((4,4'-((((R)-6-(((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)((1-(2-(2-(((2S,3S,4S,5S,6S)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-1-oxo-1-((2-(pyridin-2-yldisulfanyl)ethyl)amino)hexan-2-yl)azanediyl)bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3,2-diyl))diacetamide (Compound C1)

[0173] Into a 25-ml round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged (S)-2,6-bis(bis((1-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)hexanoic acid (A10, 500 mg, 1.0 equiv), dimethyl sulfoxide (1.5 ml), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 465 mg, 2 equiv.), and N,N-diisopropylethylamine (267 ul, 2.5 equiv.) in respective order. The reaction was aged at room temperature for 5 minutes. To the reaction mixture was added 2-(pyridin-2-yldisulfanyl) ethanamine hydrochloride (272 mg, 2 equiv.) and N,N-diisopropylethylamine (267 ul, 2.5 equiv.) in dimethyl sulfoxide (1.5 ml). The resulting mixture was aged at room temperature for 15 minutes and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product, Compound C1 (TGN-spdp), was obtained as a solid. MS(m / z): 1804.3 [M+H] +< Synthesis of TGN-S-S-peptide (Compound C2)

[0174] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged dry peptide (cglfgeieelieeglenlidwwng all(D) SEQ ID NO: 1527, 100 mg, 1 equiv.). To the reaction was added TGN-spdp (C1, 195 mg, 3 equiv.) in dimethylsulfoxide (3.2 ml). The resulting mixture was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product, Compound C2 (TGN-S-S-peptide), was obtained as a solid. MS: theoretical MW (4470.852) m / zChargeMass923.832774.41116.1244468.481488.4734468.41 Synthesis of Compounds C3a. C3b. and C4

[0175] Compounds C3a, C3b and C4 were prepared using steps and conditions as described in Scheme 4. Synthesis of Fmoc-ECL-peptide (C3a) and ECL-peptide (C3b)

[0176] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged peptide (glfgeieelieeglenlidwgng all(D), SEQ ID NO: 1074, 20 mg, 1 equiv.) in dimethyl sulfoxide (100 ul). To the reaction was added (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (13.26mg, 2.2 equiv.) in dimethylsulfoxide (100 ul). The resulting mixture was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product, Fmoc-ECL-peptide (C3a), was obtained as a solid. MS (m / z): 1587.7 (M+2, theoretical and observed)

[0177] Into a 4-dram scintillation vial was charged Fmoc-ECL-peptide (C3a, 16.29 mg, 1.0 equiv.) in dimethylformamide (500ul) and piperidine (3.11 ul, 6 equiv.) in respective order. The resulting reaction was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product, ECL-peptide (C3b), was obtained as a solid. MS (m / z): 1476.6 (M+2, theoretical), 1476.90 (M+2, observed)Synthesis of TGN-ECL-peptide (C4)

[0178] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged TetraGalNAc (A10, 25.2 mg, 4 equiv.) in dimethylformamide (193 ul), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 2.2 mg, 1.5 equiv.), and N,N-Diisopropylethylamine (DIEA, 1.7 ul, 2.5 equiv.) in respective order. The reaction was aged at room temperature for 5 minutes. To the reaction mixture was added ECL-peptide (C3b, 11.37 mg, 1 equiv.) and N,N-diisopropylethylamine (1.7 ul, 2.5 equiv.) in dimethyl sulfoxide (193 ul). The resulting mixture was aged at room temperature for 15 minutes and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in Acetonitrile. After lyophilization, the product, TGN-ECL-peptide (C4), was obtained as a solid. MS: theoretical MW (4568.86) m / z charge mass 1140.3344565.321520.7834565.34 Synthesis of Compounds C5-C8

[0179] Compounds C5-C8 were prepared using steps and conditions as described in Scheme 5. Synthesis of CDM-NHS (C5)

[0180] Into a 100-ml round bottom flask purged and maintained with an intert atmosphere of nitrogen was charged 3-(4-methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)propanoic acid (2g, 1 equiv.), 1-hydroxypyrrolidine-2,5-dione (NHS, 1.375 g, 1.1 equiv), 4-dimethylaminopyridine (DMAP, 0.066g, 0.05 equiv.), and dichloromethane (50 ml) in respective order. To the reaction was added N,N'-dicyclohexylcarbodiimide (DCC, 11.95 ml, 1.0 M in DCM, 1.1 equiv.). The resulting reaciton mixture was aged at room temperature overnight. The reaction mixture was filtered through a glass frit and concentrated in vacuo to give a tan solid which was dissolved in DCM and purified on a SiO 2 column (40 g), eluting with hexane / ethyl acetate to yield 2,5-dioxopyrrolidin-1-yl 3-(4-methyl-2,5-dioxo-2,5-dihydrofuran-3-yl)propanoate (CDM-NHS, C5) as a powder. MS (m / z): 282.1 [M+H] +< Synthesis of NH 2 -TGN (C6)

[0181] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged TetraGalNAc (A10, 323 mg, 1 equiv.) in dimethyl sulfoxide (6.55 ml), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 229 mg, 3 equiv.), and N,N-diisopropylethylamine (DIEA, 420 ul, 12 equiv.) in respective order. The reaction was aged at room temperature for 5 minutes. To the reaction mixture was added (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate (Fmoc-ethyl-diamine, 283 mg, 5 equiv.) in dimethyl sulfoxide (266 ul). The resulting reaction mixture was aged at room temperature for 5 minutes and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the resulting solid was dissolved in DMF (1ml) and added piperidine (496ul, 25 equiv.). The resulting reaction mixture was aged at room temperature for 30 minutes and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product (NH 2 -TGN, C6) was obtained as a solid. MS (m / z): 1678.7 [M+H] -< Synthesis of CDM-TGN (C7)

[0182] Into a 10-ml round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged NH 2 -TGN (C6, 195 mg, 1 equiv.) in dimethyl sulfoxide (4 ml), CDM-NHS (C5, 131.2 mg, 4 equiv.) in dimethyl sulfoxide (1.64ml), and N,N-diisopropylethylamine (DIEA, 60.9 ul, 3 equiv.) in respective order. The resulting reaction mixture was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product (CDM-TGN, C7) was obtained as a solid. MS (m / z): 1845.4 [M+H] +< Synthesis of TGN-CDM peptide (C8)

[0183] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged peptide (glfgeieelieeglenlidwgng all(D), SEQ ID NO: 1074, 2.8 mg, 1 equiv.), dimethyl sulfoxide (30 ul), 10% glucose (106 ul), 1M Hepes buffer (pH= 10.66, 160 ul) and water (56 ul) in respective order, maintaining pH at 8.85. The resulting reaction mixture was added to CDM-TGN (C7, 16.22 mg, 8 equiv.). The final pH was brought up from 8.12 to 8.5 by adding 1M Hepes buffter (150 ul). The CDM masking on the peptide was confirmed by MS and CE. MS (m / z): 1091.02 [M+4], 4368.08 observed, 4,446.698 theoretical CE: retention time at 27.234 minSynthesis of Compounds C9 and C10

[0184] Compounds C9-C10 were prepared using steps and conditions as described in Scheme 6. Synthesis of 2K-PEG-spdp (C9)

[0185] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged NHS-dPEG 49 -ester (200 mg, 1 equiv.) in dimethylsulfoxide (883 ul), 2-(pyridin-2-yldisulfanyl)ethanamine (SPDP, 40.2 mg, 2.5 equiv.) in dimethyl sulfoxide (31 ul), and N,N-diisopropylethylamine (DIEA, 136 ul, 9 equiv.) in respective order. The resulting reaction mixture was aged at room temperature for 30 minutes and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in Acetonitrile. After lyophilization, the product (2K-PEG-spdp, C9) was obtained as a solid. MS (m / z): 796.5 [M+3], 1185.8 [M+2]Synthesis of 2K-PEG-S-S-peptide (C10)

[0186] Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged peptide (cgffgeiaelieeglknlidwwng, all D, SEQ ID NO: 1692, 10 mg, 1 equiv.) and 2K-PEG-spdp (C9, 25.9 mg, 3 equiv.) in dimethyl sulfoxide (914 ul) in respective order. The resulting reaction was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on C18 column, eluting with 0.05% TFA (v / v) in water and 0.05% (v / v) TFA in acetonitrile. After lyophilization, the product (2K-PEG-S-S-peptide, C10) was obtained as a solid. MS (m / z): 1675.1[M+3], 5028.3 observed, 5,014.81 theoreticalFormulation of Peptides and siRNA Conjugates

[0187] Materials - Tris base used for buffer preparation was obtained from Promega Corporation (Madison, WI). Sucrose used for tonicity modification was acquired from Macron Fine Chemicals (Center Valley, PA). All water used for dilutions was distilled, deionized to a resistivity of 18.2 MΩ*cm and filtered through a 0.2 µm filter. Unless otherwise indicated, all other reagents were acquired and used as received from Sigma Aldrich (St. Louis, MO).

[0188] Formulation preparation for sequential dosing experiments in vivo - Prior to formulation, purified peptide and siRNA solutions were dehydrated by lyophilization at -42 °C under 40 × 10 -3< mbar for 72 h. An isotonic sucrose formulation was prepared (292 mM, 10 wt%) and sterile filtered using aseptic handling techniques in a laminar flow hood. The lyophilized peptide product was either reconstituted in the sucrose formulation (for NHP model) or water (for mouse model) and allowed to equilibrate for 12 hr at 4 °C. Rehydrated peptide was degassed via centrifugation (4000 g, 15 min) and sterile filtered using aseptic handling techniques. Following concentration analysis via UV and ICP spectroscopy (see Peptide Concentration Determination section), peptide stock solutions were diluted to target concentrations for dosing. Separately, siRNA was reconstituted in PBS and diluted to a target concentration for dosing. Both peptide and siRNA formulations were sterile filtered using aseptic handling techniques in a laminar flow hood. All formulations passed assessment for sterility and bioburden prior to dosing.

[0189] Formulation Preparation for co-dosing experiments in vivo - Similar to previous formulations, purified peptide and siRNA solutions were dehydrated by lyophilization at -42 °C under 40 × 10 -3< mbar for 72 h. Peptide and siRNA were separately rehydrated in isotonic sucrose or water for analysis in NHP or mouse models, respectively. Peptide and siRNA stocks were sterile filtered using aseptic handling techniques and stored in sterile vials. Following analytical characterization of peptide / siRNA concentration and purity, co-dosing formulation were prepared by aseptically mixing peptide, siRNA, and the isotonic sucrose solution to the target concentrations for dosing. For NHP studies, solution pH was adjusted through the addition of a sucrose-tris buffer to a final formulation composition of 292 mM sucrose, 50 mM Tris (pH 7.50). Peptide or siRNA-only experimental controls were prepared using identical procedures and formulation compositions as co-dosing groups. All formulations passed assessment for sterility and bioburden prior to dosing.Analysis of Peptides and siRNA Conjugates Peptide Concentration Determination

[0190] UV absorbance - The concentration of peptides containing Tryptophan (W), Tyrosine (Y) or Cystine residues was determined based on the summation of theoretical molar extinction coefficients of the UV active residues. UV absorbance was measured at 280 nm using a Spectramax M5e UV spectrophotometer (Molecular Devices, Sunnyvale, CA.)

[0191] Inductively Coupled Plasma Spectroscopy - The concentration of peptide in constructs containing disulfide linker chemistry was determined indirectly by quantitating the amount of sulfur present in the conjugate, using an iCAP 6000 Inductively Coupled Plasma (ICP) Spectrophotometer (Thermo Fischer, Pittsburgh, PA). Samples were diluted with water containing 1 ppm Germanium (Ge) (Ricca Chemical Company, Arlington Tx.) internal standard. After injection, the sample was introduced to Nebulizer source with RF Power 1350 W, Aux gas flow 0.5 L / min and Nebulizer Gas flow 0.65 L / min. Sulfur content was quantitated using an external standard calibration curve (ranging from 0ppm to 2 ppm ) prepared from NIST Sulfur (S) ICP standard containing 1 ppm Ge as an internal standard. Raw ppm value for sulfur was reported and final peptide concentration was calculated using the peptide to sulfur molar ratio.siRNA Concentration Determination

[0192] Inductively Coupled Plasma Spectroscopy - The concentration of siRNA in constructs was determined directly by quantitating the amount of phosphorus present in the nucleotide backbone, using an iCAP 6000 Inductively Coupled Plasma (ICP) Spectrophotometer (Thermo Fischer, Pittsburgh, PA). Samples were diluted with water containing 1 ppm Germanium (Ge) (Ricca Chemical Company, Arlington Tx.) internal standard. After injection, the sample was introduced to Nebulizer source with RF Power 1350 W, Aux gas flow 0.5 L / min and Nebulizer Gas flow 0.65 L / min. Phosphorus content was quantitated using an external standard calibration curve (ranging from 0ppm to 3 ppm ) prepared from NIST Phosphorus ICP standard containing 1 ppm Ge as an internal standard. Raw ppm value for phosphorus was reported and final siRNA concentration was calculated using the siRNA to phosphorus molar ratio.siRNA Duplex Purity

[0193] siRNA duplex purity was determined by Capillary Electrophoresis using an Agilent G1600 (Agilent Technologies Sunnyvale, Ca.). Two techniques were employed based on siRNA conjugate composition: Capillary Zone Electrophoresis (CZE) or Micellar Electrokinetic Chromatography (MEKC). The sample was hydrodynamically injected onto a bare-fused silica capillary (Agilent extended light path 25µm ID, 363 µm OD) at the anode end. The migration of analytes was initiated by applying positive 30kV to the capillary. The siRNA signal was monitored by UV detection (abs. 260 nm). siRNA duplex purity was reported by area percent; excess single strand, functional duplex impurities and free peptide also reported. All siRNA duplex were > than 85 % pure.Peptide Purity Chromatographic Conditions

[0194] Peptide purity was determined by reverse-phase high performance liquid chromatography (RP-HPLC) using a Bio Basics 4 (150 x 4.6, 5 µ particle size) column. The method conditions were as follows: Mobile Phase A: 0.1% trifluoroacetic acid (TFA) in water; Mobile Phase B: 0.1% TFA in acetonitrile; column temperature 60°C and 1 ml / min flow rate. The gradient ramped from initial conditions of 5% B to 100% B in 60 minutes, followed by an 8 minute hold and returned to initial conditions. The peptide signal was monitored using fluorescence detection (ex. 280nm and ex. 345 nm) and UV detection (abs. 214nm). Peak purity was reported by area percent. All peptide conjugates were > 70% pure.Identity by Mass Spectrometry - Methodology and Data Analysis

[0195] Peptide and RNA samples were prepared for analysis by mass spectrometry by diluting stock sample solutions with DI water to create a working solution between 30-300 µg / mL. Mobile phase A (MPA) was an aqueous solution of 100 mM hexafluoroisopropanol (HFIP) and 8 mM Triethylamine (TEA), mobile phase B (MPB) was a 90:10 (v:v) acetonitrile:water mixture. Samples were analyzed by reverse-phase UPLC separation, followed by detection by Waters Synapt quadrupole time of flight (QToF) mass spectrometer operated in negative ion mode. The column used was a Waters Acquity UPLC BEH300 C 4 column (2.1mm I.D. x 100mm length and the separation is performed at a flow rate of 0.35 mL / min at a column temperature of 65°C. The separation method starts with a 2 minute isocratic hold at 2% MPB, followed by a 5 minute gradient to 95% MPB, then another 2 minute isocratic hold at 95% MPB. The column is then equilibrated for 1 minute at 2% MPB prior to the next injection. The post-column eluent is introduced to the mass spectrometer by electrospray ionization. Data were collected ion negative ion mode between 650-4500 m / z, with no CID fragmentation. For all samples, a mass spectrum is obtained by averaging across the chromatographic peak in the MassLynx software. For RNA samples, raw mass spectra were deconvoluted from m / z to mass by using the MaxEnt1 algorithm in the MassLynx software. For peptide samples, the raw mass spectra were deconvoluted manually by determining charge states for all major peaks and calculating the resulting mass.In vitro DMD assay

[0196] Cryopreserved primary Mouse hepatocytes (Bioreclamation, LLC) were placed into Collagen Type I coated 96-well plates at 25,000 cells per well in serum-containing InVitroGRO CP media (Bioreclamation, LLC) and allowed 5 hours to attach. Media was replaced with InVitroGRO HI media and cells were treated with siRNA-IV at 125nM [siRNA] for 1 hour. Media was replaced with InVitroGRO HI media and cells were treated for approximately 16 hours with experimental Peptide conjugates at various concentrations to establish a dose-response curve. Peptide conjugates were washed out after 16 hours with InVitroGRO HI media and cells allowed to incubate for an additional 24 hours. Cells were then lysed and mRNA expression of the siRNA target was measured by RT-qPCR (Applied Biosystems Taqman reagents). mRNA silencing activity of each Peptide conjugate was expressed as an enhancement above the baseline activity of 125nM siRNA-IV alone with respect to the untreated cells and all siRNA target Ct values were normalized to PPIB mRNA for each well (dddCt) and summarized.

[0197] The structure of TGN-S-S-peptide is shown below and the activity data is listed in Table 5 (siRNA-IV concentration was kept at 125 mM). Table 5. In Vitro DataTargeted peptide Targeted peptide Dose (nM) In vitro dddCt (vs. baseline SCE dose) TGN-S-S-SEQ ID NO: 1747 (D)5000-1.98TGN-S-S-SEQ ID NO: 1747 (D)1000-2.08TGN-S-S-SEQ ID NO: 1747 (D)200-1.53TGN-S-S-SEQ ID NO: 1747 (D)40-0.7TGN-S-S-SEQ ID NO: 1747 (D)8-0.23TGN-S-S-SEQ ID NO: 1748 (D)5000-2.01TGN-S-S-SEQ ID NO: 1748 (D)1000-1.92TGN-S-S-SEQ ID NO: 1748 (D)200-1.38TGN-S-S-SEQ ID NO: 1748 (D)40-0.5TGN-S-S-SEQ ID NO: 1748 (D)8-0.2TGN-S-S-SEQ ID NO: 1749 (D)5000-0.11TGN-S-S-SEQ ID NO: 1749 (D)1000-0.22TGN-S-S-SEQ ID NO: 1749 (D)200-0.26TGN-S-S-SEQ ID NO: 1749 (D)40-0.04TGN-S-S-SEQ ID NO: 1749 (D)80.02TGN-S-S-SEQ ID NO: 1751 (D)50000.01TGN-S-S-SEQ ID NO: 1751 (D)1000-0.05TGN-S-S-SEQ ID NO: 1751 (D)2000.09TGN-S-S-SEQ ID NO: 1751 (D)40-0.12TGN-S-S-SEQ ID NO: 1751 (D)8-0.1TGN-S-S-SEQ ID NO: 1752 (D)5000-1.02TGN-S-S-SEQ ID NO: 1752 (D)1000-0.95TGN-S-S-SEQ ID NO: 1752 (D)200-0.89TGN-S-S-SEQ ID NO: 1752 (D)40-0.48TGN-S-S-SEQ ID NO: 1752 (D)8-0.25TGN-S-S-SEQ ID NO: 1753 (D)5000-0.16TGN-S-S-SEQ ID NO: 1753 (D)1000-0.18TGN-S-S-SEQ ID NO: 1753 (D)200-0.2TGN-S-S-SEQ ID NO: 1753 (D)400.05TGN-S-S-SEQ ID NO: 1753 (D)80.15TGN-S-S-SEQ ID NO: 1755 (D)5000-0.24TGN-S-S-SEQ ID NO: 1755 (D)1000-0.49TGN-S-S-SEQ ID NO: 1755 (D)200-0.38TGN-S-S-SEQ ID NO: 1755 (D)40-0.24TGN-S-S-SEQ ID NO: 1755 (D)8-0.01TGN-S-S-SEQ ID NO: 1756 (D)5000-0.95TGN-S-S-SEQ ID NO: 1756 (D)1000-1.05TGN-S-S-SEQ ID NO: 1756 (D)200-0.76TGN-S-S-SEQ ID NO: 1756 (D)40-0.4TGN-S-S-SEQ ID NO: 1756 (D)8-0.15TGN-S-S-SEQ ID NO: 1758 (D)5000-0.64TGN-S-S-SEQ ID NO: 1758 (D)1000-0.77TGN-S-S-SEQ ID NO: 1758 (D)200-0.38TGN-S-S-SEQ ID NO: 1758 (D)40-0.02TGN-S-S-SEQ ID NO: 1758 (D)80.04TGN-S-S-Seq-ID-88 (D)5000-1.7TGN-S-S-SEQ ID NO: 1759 (D)1000-1.66TGN-S-S-SEQ ID NO: 1759 (D)200-1.65TGN-S-S-SEQ ID NO: 1759 (D)40-0.87TGN-S-S-SEQ ID NO: 1759 (D)8-0.15TGN-S-S-SEQ ID NO: 1760 (D)5000-1.46TGN-S-S-SEQ ID NO: 1760 (D)1000-1.8TGN-S-S-SEQ ID NO: 1760 (D)200-1.6TGN-S-S-SEQ ID NO: 1760 (D)40-1.01TGN-S-S-SEQ ID NO: 1760 (D)8-0.09TGN-S-S-SEQ ID NO: 1761 (D)5000-0.11TGN-S-S-SEQ ID NO: 1761 (D)1000-0.07TGN-S-S-SEQ ID NO: 1761 (D)200-0.22TGN-S-S-SEQ ID NO: 1761 (D)40-0.25TGN-S-S-SEQ ID NO: 1761 (D)80.08TGN-S-S-SEQ ID NO: 1762 (D)5000-0.08TGN-S-S-SEQ ID NO: 1762 (D)1000-0.39TGN-S-S-SEQ ID NO: 1762 (D)200-0.17TGN-S-S-SEQ ID NO: 1762 (D)400.03TGN-S-S-SEQ ID NO: 1762 (D)8-0.07TGN-S-S-SEQ ID NO: 1763 (D)5000-1.29TGN-S-S-SEQ ID NO: 1763 (D)1000-1.44TGN-S-S-SEQ ID NO: 1763 (D)200-1.26TGN-S-S-SEQ ID NO: 1763 (D)40-0.67TGN-S-S-SEQ ID NO: 1763 (D)8-0.13TGN-S-S-SEQ ID NO: 1764 (D)5000-0.75TGN-S-S-SEQ ID NO: 1764 (D)1000-0.62TGN-S-S-SEQ ID NO: 1764 (D)200-0.78TGN-S-S-SEQ ID NO: 1764 (D)40-0.41TGN-S-S-SEQ ID NO: 1764 (D)8-0.03TGN-S-S-SEQ ID NO: 1765(D)5000-1.23TGN-S-S-SEQ ID NO: 1765(D)1000-1.23TGN-S-S-SEQ ID NO: 1765(D)200-0.88TGN-S-S-SEQ ID NO: 1765(D)40-0.38TGN-S-S-SEQ ID NO: 1765(D)8-0.04TGN-S-S-SEQ ID NO: 1766 (D)5000-0.45TGN-S-S-SEQ ID NO: 1766 (D)1000-0.49TGN-S-S-SEQ ID NO: 1766 (D)200-0.31TGN-S-S-SEQ ID NO: 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(L)5000-0.79TGN-S-S-Seq-ID-37 (L)1000-0.19TGN-S-S-Seq-ID-37 (L)200-0.01TGN-S-S-Seq-ID-37 (L)400.14TGN-S-S-Seq-ID-37 (L)80.02TGN-S-S-Seq-ID-40 (L)5000-0.2TGN-S-S-Seq-ID-40 (L)1000-0.12TGN-S-S-Seq-ID-40 (L)200-0.12TGN-S-S-Seq-ID-40 (L)40-0.07TGN-S-S-Seq-ID-40 (L)8-0.14TGN-S-S-Seq-ID-41 (L)5000-0.11TGN-S-S-Seq-ID-41 (L)1000-0.2TGN-S-S-Seq-ID-41 (L)200-0.06TGN-S-S-Seq-ID-41 (L)40-0.14TGN-S-S-Seq-ID-41 (L)8-0.11TGN-S-S-Seq-ID-45 (L)5000-0.26TGN-S-S-Seq-ID-45 (L)1000-0.01TGN-S-S-Seq-ID-45 (L)200-0.08TGN-S-S-Seq-ID-45 (L)400.04TGN-S-S-Seq-ID-45 (L)8-0.14TGN-S-S-Seq-ID-50 (D)5000-0.3TGN-S-S-Seq-ID-50 (D)1000-0.17TGN-S-S-Seq-ID-50 (D)2000.07TGN-S-S-Seq-ID-50 (D)400.03TGN-S-S-Seq-ID-50 (D)8-0.01TGN-S-S-Seq-ID-53 (L)50000.01TGN-S-S-Seq-ID-53 (L)1000-0.02TGN-S-S-Seq-ID-53 (L)200-0.11TGN-S-S-Seq-ID-53 (L)40-0.08TGN-S-S-Seq-ID-53 (L)8-0.11TGN-S-S-Seq-ID-54 (L)50000.07TGN-S-S-Seq-ID-54 (L)1000-0.03TGN-S-S-Seq-ID-54 (L)200-0.16TGN-S-S-Seq-ID-54 (L)40-0.07TGN-S-S-Seq-ID-54 (L)80.03TGN-S-S-Seq-ID-55 (L)5000-0.01TGN-S-S-Seq-ID-55 (L)10000.05TGN-S-S-Seq-ID-55 (L)2000.12TGN-S-S-Seq-ID-55 (L)400.08TGN-S-S-Seq-ID-55 (L)80.11TGN-S-S-Seq-ID-56 (L)5000-0.58TGN-S-S-Seq-ID-56 (L)1000-0.08TGN-S-S-Seq-ID-56 (L)200-0.12TGN-S-S-Seq-ID-56 (L)400.05TGN-S-S-Seq-ID-56 (L)80.02TGN-S-S-Seq-ID-57 (L)50000.09TGN-S-S-Seq-ID-57 (L)10000.1TGN-S-S-Seq-ID-57 (L)2000.02TGN-S-S-Seq-ID-57 (L)400TGN-S-S-Seq-ID-57 (L)80.1TGN-S-S-Seq-ID-58 (D)5000-0.3TGN-S-S-Seq-ID-58 (D)1000-0.26TGN-S-S-Seq-ID-58 (D)200-0.25TGN-S-S-Seq-ID-58 (D)40-0.03TGN-S-S-Seq-ID-58 (D)8-0.05TGN-S-S-Seq-ID-59 (D)50000.25TGN-S-S-Seq-ID-59 (D)10000.17TGN-S-S-Seq-ID-59 (D)200-0.02TGN-S-S-Seq-ID-59 (D)40-0.03TGN-S-S-Seq-ID-59 (D)8-0.13TGN-S-S-Seq-ID-61 (D)5000-0.55TGN-S-S-Seq-ID-61 (D)10000TGN-S-S-Seq-ID-61 (D)2000.01TGN-S-S-Seq-ID-61 (D)400.08TGN-S-S-Seq-ID-61 (D)80.13TGN-S-S-Seq-ID-65 (D)5000-2.68TGN-S-S-Seq-ID-65 (D)1000-1.88TGN-S-S-Seq-ID-65 (D)200-1.48TGN-S-S-Seq-ID-65 (D)40-0.73TGN-S-S-Seq-ID-65 (D)80TGN-S-S-Seq-ID-29 (D)5000-0.72TGN-S-S-Seq-ID-29 (D)1000-0.52TGN-S-S-Seq-ID-29 (D)200-0.44TGN-S-S-Seq-ID-29 (D)40-0.12TGN-S-S-Seq-ID-29 (D)80.05TGN-S-S-Seq-ID-28 (D)5000-1.67TGN-S-S-Seq-ID-28 (D)1000-1.65TGN-S-S-Seq-ID-28 (D)200-1.47TGN-S-S-Seq-ID-28 (D)40-1.14TGN-S-S-Seq-ID-28 (D)8-0.27TGN-S-S-Seq-ID-27 (D)5000-0.65TGN-S-S-Seq-ID-27 (D)1000-0.61TGN-S-S-Seq-ID-27 (D)200-0.53TGN-S-S-Seq-ID-27 (D)40-0.38TGN-S-S-Seq-ID-27 (D)8-0.05TGN-S-S-Seq-ID-26 (D)5000-0.69TGN-S-S-Seq-ID-26 (D)10000.12TGN-S-S-Seq-ID-26 (D)2000.21TGN-S-S-Seq-ID-26 (D)400.1TGN-S-S-Seq-ID-26 (D)80.1TGN-S-S-Seq-ID-25 (D)5000-1.72TGN-S-S-Seq-ID-25 (D)10000.01TGN-S-S-Seq-ID-25 (D)200-0.13TGN-S-S-Seq-ID-25 (D)400.2TGN-S-S-Seq-ID-25 (D)8-0.06TGN-S-S-SEQ ID NO: 1710 (D)5000-3.12TGN-S-S-SEQ ID NO: 1710 (D)1000-2.83TGN-S-S-SEQ ID NO: 1710 (D)200-2TGN-S-S-SEQ ID NO: 1710 (D)40-1.04TGN-S-S-SEQ ID NO: 1710 (D)8-0.2TGN-S-S-SEQ ID NO: 1732(D)31250.67TGN-S-S-SEQ ID NO: 1732(D)6250.66TGN-S-S-SEQ ID NO: 1732(D)1250.47TGN-S-S-SEQ ID NO: 1732(D)250.47TGN-S-S-SEQ ID NO: 1078 (D)3125-1.06TGN-S-S-SEQ ID NO: 1078 (D)625-0.96TGN-S-S-SEQ ID NO: 1078 (D)125-0.82TGN-S-S-SEQ ID NO: 1078 (D)25-0.34TGN-S-S-SEQ ID NO: 1633 (D)3125-0.2TGN-S-S-SEQ ID NO: 1633 (D)625-0.2TGN-S-S-SEQ ID NO: 1633 (D)25-0.33TGN-S-S-SEQ ID NO: 1703 (D)3125-0.57TGN-S-S-SEQ ID NO: 1703 (D)625-0.43TGN-S-S-SEQ ID NO: 1703 (D)125-0.38TGN-S-S-SEQ ID NO: 1703 (D)25-0.09TGN-S-S-SEQ ID NO: 1654 (D)3125-1.48TGN-S-S-SEQ ID NO: 1654 (D)625-1.3TGN-S-S-SEQ ID NO: 1654 (D))125-1.05TGN-S-S-SEQ ID NO: 1654 (D)25-0.39TGN-S-S-SEQ ID NO: 1631 (D)3125-0.37TGN-S-S-SEQ ID NO: 1631 (D)6250.07TGN-S-S-SEQ ID NO: 1631 (D)1250.25TGN-S-S-SEQ ID NO: 1704 (D)3125-0.39TGN-S-S-SEQ ID NO: 1704 (D)625-0.56TGN-S-S-SEQ ID NO: 1704 (D)125-0.32TGN-S-S-SEQ ID NO: 1704 (D)25-0.08TGN-S-S-SEQ ID NO: 1653 (D)3125-2.46TGN-S-S-SEQ ID NO: 1653 (D)625-1.97TGN-S-S-SEQ ID NO: 1653 (D)125-1.45TGN-S-S-SEQ ID NO: 1653 (D)25-0.76TGN-S-S-SEQ ID NO: 1717 (L)31250.15TGN-S-S-SEQ ID NO: 1717 (L)6250.37TGN-S-S-SEQ ID NO: 1717 (L)250.61TGN-S-S-SEQ ID NO: 1705 (D)3125-0.17TGN-S-S-SEQ ID NO: 1705 (D)625-0.69TGN-S-S-SEQ ID NO: 1705 (D)125-0.21TGN-S-S-SEQ ID NO: 1705 (D)25-0.06TGN-S-S-SEQ ID NO: 1706 (D)3125-1.01TGN-S-S-SEQ ID NO: 1706 (D)625-1.05TGN-S-S-SEQ ID NO: 1706 (D)125-0.95TGN-S-S-SEQ ID NO: 1706 (D)25-0.77TGN-S-S-SEQ ID NO: 1730 (D)3125-3.38TGN-S-S-SEQ ID NO: 1730 (D)625-0.67TGN-S-S-SEQ ID NO: 1730 (D)1250.15TGN-S-S-SEQ ID NO: 1730 (D)250.44TGN-S-S-SEQ ID NO: 1707 (D)3125-0.39TGN-S-S-SEQ ID NO: 1707 (D)625-0.54TGN-S-S-SEQ ID NO: 1707 (D)125-0.21TGN-S-S-SEQ ID NO: 1707 (D)25-0.35TGN-S-S-SEQ ID NO: 1647 (D)3125-0.21TGN-S-S-SEQ ID NO: 1647 (D)625-0.41TGN-S-S-SEQ ID NO: 1647 (D)125-0.32TGN-S-S-SEQ ID NO: 1647 (D)25-0.05TGN-S-S-SEQ ID NO: 1720 (L)625-0.57TGN-S-S-SEQ ID NO: 1720 (L)1250.13TGN-S-S-SEQ ID NO: 1720 (L)250.04TGN-S-S-SEQ ID NO: 1733 (D)3125-1.93TGN-S-S-SEQ ID NO: 1733 (D)625-1.92TGN-S-S-SEQ ID NO: 1733 (D)125-1.16TGN-S-S-SEQ ID NO: 1733 (D)25-0.85TGN-S-S-SEQ ID NO: 1701 (D)3125-1.69TGN-S-S-SEQ ID NO: 1701 (D)625-1.46TGN-S-S-SEQ ID NO: 1701 (D)125-1.55TGN-S-S-SEQ ID NO: 1701 (D)25-0.58TGN-S-S-SEQ ID NO: 1518 (L)31250.19TGN-S-S-SEQ ID NO: 1518 (L)6250.3TGN-S-S-SEQ ID NO: 1518 (L)1250.37TGN-S-S-SEQ ID NO: 1518 (L)250.54TGN-S-S-SEQ ID NO: 1734 (D)3125-1.14TGN-S-S-SEQ ID NO: 1734 (D)625-0.86TGN-S-S-SEQ ID NO: 1734 (D)125-0.42TGN-S-S-SEQ ID NO: 1734 (D)25-0.2TGN-S-S-SEQ ID NO: 1628 (D)3125-2.24TGN-S-S-SEQ ID NO: 1628 (D)625-1.64TGN-S-S-SEQ ID NO: 1628 (D)125-1.17TGN-S-S-SEQ ID NO: 1628 (D)25-0.54TGN-S-SEQ ID NO: 1517 (L)31250.33TGN-S-SEQ ID NO: 1517 (L)6250.48TGN-S-SEQ ID NO: 1517 (L)1250.49TGN-S-SEQ ID NO: 1517 (L)250.54TGN-S-S-SEQ ID NO: 1652 (D)15625-2.03TGN-S-S-SEQ ID NO: 1652 (D)3125-1.6TGN-S-S-SEQ ID NO: 1652 (D)625-1.5TGN-S-S-SEQ ID NO: 1652 (D)125-1.27TGN-S-S-SEQ ID NO: 1701 (D)15625-2.15TGN-S-S-SEQ ID NO: 1701 (D)3125-1.65TGN-S-S-SEQ ID NO: 1701 (D)625-1.35TGN-S-S-SEQ ID NO: 1701 (D)125-1.14TGN-S-S-SEQ ID NO: 1078(D)15625-1.44TGN-S-S-SEQ ID NO: 1078(D)3125-1.17TGN-S-S-SEQ ID NO: 1078(D)625-1.24TGN-S-S-SEQ ID NO: 1078(D)125-1.04TGN-S-S-SEQ ID NO: 1651 (D)15625-1.48TGN-S-S-SEQ ID NO: 1651 (D)3125-1.55TGN-S-S-SEQ ID NO: 1651 (D)625-1.11TGN-S-S-SEQ ID NO: 1651 (D)125-0.84TGN-S-S-SEQ ID NO: 1628 (D)15625-2.67TGN-S-S-SEQ ID NO: 1628 (D)3125-2.15TGN-S-S-SEQ ID NO: 1628 (D)625-1.86TGN-S-S-SEQ ID NO: 1628 (D)125-1.17TGN-S-S- SEQ ID NO: 166215625-0.45TGN-S-S- SEQ ID NO: 16623125-0.48TGN-S-S- SEQ ID NO: 1662625-0.47TGN-S-S- SEQ ID NO: 1662125-0.31TGN-S-S-SEQ ID NO: 1650 (D)15625-0.57TGN-S-S-SEQ ID NO: 1650 (D)3125-0.21TGN-S-S-SEQ ID NO: 1650 (D)625-0.45TGN-S-S-SEQ ID NO: 1650 (D)125-0.33TGN-S-S-SEQ ID NO: 1633(D)15625-0.69TGN-S-S-SEQ ID NO: 1633(D)3125-0.37TGN-S-S-SEQ ID NO: 1633(D)625-0.57TGN-S-S-SEQ ID NO: 1633(D)125-0.39TGN-S-S- SEQ ID NO: 169615625-0.54TGN-S-S- SEQ ID NO: 16963125-0.4TGN-S-S- SEQ ID NO: 1696625-0.59TGN-S-S- SEQ ID NO: 1696125-0.41TGN-S-S-SEQ ID NO: 1632 (D)15625-0.47TGN-S-S-SEQ ID NO: 1632 (D)3125-0.19TGN-S-S-SEQ ID NO: 1632 (D)625-0.44TGN-S-S-SEQ ID NO: 1632 (D)125-0.29TGN-S-S-SEQ ID NO: 1657 (D)15625-0.56TGN-S-S-SEQ ID NO: 1657 (D)3125-0.4TGN-S-S-SEQ ID NO: 1657 (D)625-0.49TGN-S-S-SEQ ID NO: 1657 (D)125-0.42TGN-S-S-SEQ ID NO: 1634 (D)15625-0.74TGN-S-S-SEQ ID NO: 1634 (D)3125-0.3TGN-S-S-SEQ ID NO: 1634 (D)625-0.41TGN-S-S-SEQ ID NO: 1634 (D)125-0.3TGN-S-S-SEQ ID NO: 1660(D)15625-0.7TGN-S-S-SEQ ID NO: 1660(D)3125-0.69TGN-S-S-SEQ ID NO: 1660(D)625-0.9TGN-S-S-SEQ ID NO: 1660(D)125-0.57TGN-S-S-SEQ ID NO: 1649 (D)15625-0.77TGN-S-S-SEQ ID NO: 1649 (D)3125-0.61TGN-S-S-SEQ ID NO: 1649 (D)625-0.48TGN-S-S-SEQ ID NO: 1649 (D)125-0.3TGN-S-S-SEQ ID NO: 1631 (D)15625-2.11TGN-S-S-SEQ ID NO: 1631 (D)3125-0.45TGN-S-S-SEQ ID NO: 1631 (D)625-0.3TGN-S-S-SEQ ID NO: 1631 (D)125-0.19TGN-S-S-SEQ ID NO: 1654 (D)15625-1.61TGN-S-S-SEQ ID NO: 1654 (D)3125-1.48TGN-S-S-SEQ ID NO: 1654 (D)625-1.08TGN-S-S-SEQ ID NO: 1654 (D)125-1.05TGN-S-S-SEQ ID NO: 1648 (D)15625-0.59TGN-S-S-SEQ ID NO: 1648 (D)3125-0.39TGN-S-S-SEQ ID NO: 1648 (D)625-0.57TGN-S-S-SEQ ID NO: 1648 (D)125-0.27TGN-S-S-SEQ ID NO: 255 (D)625-1.59TGN-S-S-SEQ ID NO: 255 (D)125-0.37TGN-S-S-SEQ ID NO: 1653 (D)15625-2.13TGN-S-S-SEQ ID NO: 1653 (D)3125-1.92TGN-S-S-SEQ ID NO: 1653 (D)625-1.53TGN-S-S-SEQ ID NO: 1653 (D)125-1.31TGN-S-S-SEQ ID NO: 1647 (D)15625-0.68TGN-S-S-SEQ ID NO: 1647 (D)3125-0.58TGN-S-S-SEQ ID NO: 1647 (D)625-0.59TGN-S-S-SEQ ID NO: 1647 (D)125-0.52Note: Every amino acid (except glycine) can occur in two isomeric forms, because of the possibility of forming two different enantiomers (stereoisomers) around the central carbon atom. By convention, these are called L- and D- forms, analogous to left-handed and right-handed configurations. In Vivo Assay - In Vivo Evaluation in Mice:

[0198] Female CD-1 mice (Charles River) were injected in accordance with either a sequential dosing paradigm or a co-dosing paradigm. In the sequential dosing paradigm, the targeted siRNA (SCE) is dosed at t=0 and the targeted peptide is separately dosed up to 2 hr before the SCE (-2 hr) or up to 24 hr after the SCE (+24 hr). In the co-dosing paradigm, the SCE and peptides are co-formulated and dosed together in the same formulation as a single injection at t=0. The mice were dosed either by intravenous (i.v.) or subcutaneous (s.c.) injection of SCE and peptide. For the i.v. doses, the compounds were injected into the tail vein of the mice. For the s.c. doses, the compounds were injected in the subcutaneous space on the back of the mouse between the shoulder blades. At the indicated harvest times (measured from t=0 when the siRNA was dosed, regardless of when the peptide was dosed), the animals were sacrificed and 3 mm liver punches were collected, preserved in RNAlater (Ambion), and stored at 4°C. Separate 5 mm liver punches were collected, placed in 96-well plates, frozen on dry ice, and stored at -80°C until use.mRNA Knockdown Measurement:

[0199] The 3 mm liver punches were removed from RNAlater and homogenized in Trizol (Invitrogen) using a bead mill tissue lyser (Qiagen); disruption was performed for two 5-minute cycles at 30 Hz. RNA extraction was performed using 1-bromo-2-chloropropane (Acros Organics) and total RNA was isolated from the aqueous phase using the MagMax RNA isolation method (Ambion). RNA (125 ng) was reverse transcribed using the High Capacity cDNA Reverse Transcription kit (Applied Biosystems). TaqMan qPCR analysis was performed with an ABI 7900 Real-Time PCR System using TaqMan Fast Advanced Master Mix (Applied Biosystems). All TaqMan probes and primers for CTNNB 1 and PPIB (housekeeping gene) were purchased from Applied Biosystems as pre-validated gene expression assays. Results are calculated by the comparative Ct method, where the difference between the CTNNB1 Ct value and the PPIB Ct value (ΔCt) is calculated and then further normalized relative to the PBS control by taking a second difference (ΔΔCt), as described previously (1).

[0200] Table-3, shows the mRNA knockdown data of multiple peptide conjugates dosed sequentially with peptide dosed 15 min after siRNA via intravenous (IV) routeStem-loop qPCR:

[0201] The same liver homogenates used to measure mRNA knockdown were also used to measure the concentration of CTNNB1 siRNA in the liver using a modified quantitative stem-loop RT-PCR protocol (2). Liver homogenate samples were diluted in TE buffer and then the antisense strand of the siRNA (5'-UUUCGAAUCAAUCCAACAGUU-3'; Seq. ID No. 1810) was reverse transcribed with 25 nM of a CTNNB1-specific stem-loop primer (5'-GTCGTATCCAGTGCAGGGTCCGAGGTATTCGCACTGGATACGACAACTGTTG-3'; Seq. ID No. 1811) using a TaqMan MicroRNA reverse transcription kit (Applied Biosystems) using 0.5 µL MultiScribe RT enzyme per reaction. A standard curve was generated by spiking CTNNB1 siRNA into untreated liver homogenate and then serially diluting with TE buffer. The cDNA from the RT step was utilized for real-time PCR using TaqMan Universal Master Mix (Applied Biosystems) with 1.5 µM of forward primer (5'-GGCGG CTTTCGAATCAATCCA-3'; Seq. ID No. 1812), 0.75 µM of reverse primer (5'-AGTGCAGGGTCCGAG-3'; Seq. ID No. 1813), and 0.2 µM of probe (5'-6FAM-TGGATACGACAACTGTTG-3'; Seq. ID No. 1814). Quantitative PCR reactions were performed using standard cycling conditions in an ABI 7900HT Fast Real-Time PCR System. Normalized Ct values were transformed into plasma concentrations using the linear equation derived from the standard curve.Quantitation of siRNA Bound to RISC:

[0202] The 5 mm liver punches were homogenized in lysis buffer (50 mM Tris, 200 mM NaCl, 2 mM EDTA, 0.5% Triton-X-100, 1 mg / mL heparin, 1 tablet / 50 mL of cOmplete EDTA-free protease inhibitor cocktail, and 200 U / mL benzonase), using a Geno / Grinder (SPEX SamplePrep Corp) with a stainless steel grinding ball (5 / 32", 4mm SPEX SamplePrep Corp) in a 96-well plate at 1100 strokes per minute for five intervals of one min each at 4°C. Samples were then centrifuged at 14,000 rpm for 30 min at 4°C and protein levels were determined using a Peirce BCA Kit. Mouse anti mouse Ago2 monoclonal antibody (018-22021, Wako) was bound to magnetic beads (Invitrogen Dynabeads Protein G) in a 96-well microtiter plate. Liver lysates were incubated overnight at 4°C with the antibody-magnetic bead complex. Post-incubation the samples were washed, incubated with 10 U / mL of benzonase (Sigma Aldrich) to reduce background, resuspended in 0.01% NP-40 detergent, and eluted off of the magnetic bead using heat (95°C for 15 min). Using the 0.01% NP-40 samples, the antisense strand of the siRNA was quantitated using the stem-loop procedure described above, except that the standard curve was generated by spiking CTNNB siRNA into 0.01% NP-40 and then serially diluting with 0.01% NP-40. Simultaneously, the 0.01% NP-40 samples were used to quantitate miR-16 (5'-UAGCAGCACGUAAAUAUUGGCG-3'; Seq. ID No. 1815) using TaqMan MicroRNA Assay hsa-mir-16 (Applied Biosystems assay ID 000391) following the manufacturer's kit instructions. A standard curve was generated by spiking miR-16 into 0.01% NP-40 and then serially diluting with 0.01% NP-40. Quantitative PCR reactions were performed using standard cycling conditions in an ABI 7900HT Fast Real-Time PCR System. Normalized Ct values were transformed into liver concentrations using the linear equation derived from the standard curve. Using the concentrations derived from the standard curves of both the CTNNB1 siRNA and the miR-16, a ratio of RISC-bound siRNA to RISC-bound miR-16 was determined.In Vivo Evaluation in Non-Human Primates:

[0203] Chair-trained rhesus monkeys were dosed with siRNA at t=0 by i.v. injection into the saphenous vein and then dosed with peptide (or sucrose buffer) by i.v. injection into the saphenous vein 15 min later. At indicated harvest times, monkeys were sedated using ketamine and / or telazol (5-30 mg / kg or 4-6 mg / kg, respectively) and then a ~500 mg liver biopsy sample was obtained during a minimally invasive surgery (MIS) procedure. The liver tissue was stored in RNAlater and processed for mRNA knockdown as described above. The liver tissue was also processed for stem-loop qPCR and RISC binding as described above. The only differences were that rhesus-specific TaqMan probes and primers for CTNNB1 and PPIB (housekeeping gene) were purchased from Applied Biosystems and that a mouse anti human Ago2 monoclonal antibody (018-22033, Wako) was used during the immunoprecipitation step in the RISC analysis

[0204] The structure of TGN-S-S-peptide is the same as that shown above for Table 5 and the structure of TGN-L-siRNA is shown below. The activity data is listed in Table 6. Table 6. mRNA Knockdown Data - Sequential Dosing with Peptide Dosed 15 min After siRNA via Intravenous (IV) RouteTargeted Targeted Targeted siRNA Targeted peptide In vivo mRNA siRNA peptide dose-IV (mg / kg) dose-IV (mg / kg) knockdown (%) siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)5266siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)51079siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)2258siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)21064siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)0.5230siRNA-IVTGN-S-S-SEQ ID NO: 1710 (D)0.51067siRNA-IV-5035siRNA-IV-2025siRNA-IV-0.5025TGN-L-siRNA-III-0.5030TGN-L-siRNA-III-0.25015TGN-LsiRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.52563TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.51868TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.251069TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.25550TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1643 (D)0.251041TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1078 (D)0.251053TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1662 (D)0.251032TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1696 (D)0.251044TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1657 (D)0.251035TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1660 (D)0.251034TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)0.25251TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)0.251072TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)0.2550*65TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1653 (D)0.255069TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1653 (D)0.251063TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1652 (D)0.251037TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1651 (D)0.251049TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1650 (D)0.251049TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1649 (D)0.251041TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1648 (D)0.251041TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1647 (D)0.251029TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)0.25257TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)0.251068TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)0.252577TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)0.2550*82TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1645 (D)0.251037TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1628 (D)0.2510*All mice diedTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1633 (D)0.251055TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1632 (D)0.251036TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1634 (D)0.251017TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1631 (D)0.251017TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1697 (D)0.251052TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1702(D)0.25575TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1703 (D)0.25554TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1704 (D)0.25564TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1705 (D)0.25559TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1706 (D)0.25561TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1707 (D)0.25556TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1708 (L)0.25546TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (L)0.5516TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710(L)0.5521TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1711 (L)0.5536TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1712 (L)0.5534TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1713 (L)0.2520TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1713 (L)0.25102TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1715 (L)0.5528TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1716 (L)0.5539TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1717(L)0.5516TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1718 (L)0.25106TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1719 (L)0.25525TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1403 (L)0.25222TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1403(L)0.251024TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1518(L)0.25218.3TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1518 (L)0.251013TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1517 (L)0.252,18TGN-L-siRNA-IIITGN-S-S- SEQ ID NO: 1517 (L)0.251018TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1516 (L)0.25514TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 935 (L)0.25217TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 935 (L)0.251023TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1391 (L)0.5106TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (L)0.5524TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1720 (L)0.51031TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1721 (L)0.5108TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1722 (L)0.51021TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1723 (L)0.5105TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1724 (L)0.51021TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1725 (L)0.251019TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1726(D)0.251023TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1727 (D)0.251026TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1728(D)0.251023TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1729 (L)0.251010TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1730 (D)0.251043TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1731(D)0.251030TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1732 (D)0.255TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1733 (D)0.25573TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1734 (D)0.25561TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1732 (D)0.25535TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)0.25160TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)0.25375TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)0.251058TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)0.255050TGN-L-siRNA-IITGN-S-S- SEQ ID NO: 1738 (D)0.25125TGN-L-siRNA-IITGN-S-S- SEQ ID NO: 1738 (D)0.25344TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1740 (L)0.25320TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1741(L)0.25324TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1740 (D)0.25123TGN-L-siRNA-IITGN-S-S- SEQ ID NO: 1740 (D)0.25342TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)0.25254TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)0.251065TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)0.252577TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)0.253581TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1744 (D)0.5228TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1744 (D)0.51033TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)0.5254TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)0.51069TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)0.52566TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1746 (D)0.5231TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1746 (D)0.51025TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1489 (D)0.5237TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1489 (D)0.51026TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1489 (D)0.52534TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)0.5243TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)0.51078TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)0.525*76TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)0.5242TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)0.51074TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)0.525*58TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.50.526TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5240TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5565TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.51070TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)0.50.526TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)0.5244TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)0.5551TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)0.51068TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)0.50.540TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)0.5242TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)0.5550TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)0.51060TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)0.50.535TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)0.5260TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)0.5565TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)0.51075TGN-L-siRNA-I-0.5020TGN-L-siRNA-I2K-PEG-S-S-Seq-ID-50 (D)0.50.522TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 26 (D)0.5225TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 26 (D)0.5545TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 26 (D)0.51045TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 74 (D)0.50.520TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 74 (D)0.5220TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 74 (D)0.5520TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 74 (D)0.51020TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 82 (D)0.5215TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 82 (D)0.5530TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 82 (D)0.51045TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 1710 (D)0.5225TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 1710 (D)0.5515TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 1710 (D)0.51025TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 543 (D)0.5225TGN-L-siRNA-I2K-PEG-S-S-SEQ ID NO: 543 (D)0.5525Note: D - D isomer of peptide; L - L isomer of peptide; 2K-S-S-PEG-SEQ ID NO = 2K-PEG-S-S-peptide; * lethal at this dose Comparison of Sequential Dosing (Peptide Dosed 15 min after siRNA) vs. Co-dosing and Comparison of SC vs. IV Dosing

[0205] The structure of TGN-S-S-peptide is the same as that shown above for Table 5 and the structure of TGN-L-siRNA is the same as that shown above for Table 6. The activity data is listed in Table 7. Table 7. (i) Comparison of sequential dosing (peptide dosed 15 min after siRNA) vs. co-dosing (ii) Comparison of s.c. vs. i.v. dosingTargeted siRNA Targeted peptide Targeted siRNA dose (mg / kg) Targeted peptide dose (mg / kg) In vivo mRNA Route of knockdown (%) administration TGN-L-siRNA-III0.5040IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5230Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5560Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.51070Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5230Sequential dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5525Sequential dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.51025Sequential dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.5260Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.5566Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.51075Sequential dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.5265Sequential dosing-SCTGN-L-siRNA-IIITGN-S-SSEQ ID NO: 1710(D)0.5564Sequential dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)0.51066Sequential dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5230Co-dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5560Co-dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.51070Co-dosing-IVTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5230Co-dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.5525Co-dosing-SCTGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)0.51025Co-dosing-SCTGN-L-siRNA-II-0.5025SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D)0.5266Co-dosing -SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D)0.51077Co-dosing -SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D)0.5254Sequential dosing-SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D)0.51072Sequential dosing-SCTGN-L-siRNA-II-0.25025IVTGN-L-siRNA-II-0.2509SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733 (D)0.25369Sequential dosing-IVTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733 (D)0.251058Sequential dosing-IVTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733 (D)0.25347Sequential dosing-SCTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733 (D)0.251067Sequential dosing-SCNote: D - D isomer of peptide. Comparison of Disulfide vs. ECL vs. CDM Linkages between Targeting Ligand and Peptide

[0206] The structure of TGN-S-S-peptide is the same as that shown above for Table 5 and the structure of TGN-L-siRNA is the same as that shown above for Table 6. The activity data is listed in Table 8. Table 8: Comparison of Disulfide vs. ECL vs. CDM Linkages between Targeting Ligand and PeptideTargeted siRNA Targeted peptide Targeted siRNA dose (mg / kg) Targeted peptide dose (mg / kg) In vivo mRNA knockdown (%) Peptide sequence TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1745 (D)0.25346.1cglfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1745 (D)0.25144.4cglfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-ECL-SEQ ID NO: 1801 (D)0.25347.4glfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-ECL-SEQ ID NO: 1801 (D)0.25129.6glfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-CDM-SEQ ID NO: 1801 (D)0.25324.9glfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-CDM-SEQ ID NO: 1801 (D)0.25123.0glfgeieelieeglenlidwgngTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 74 (D)0.25333.9cffgaiwefihsilTGN-L-siRNA-IITGN-S-S-SEQ ID NO: 74 (D)0.25115.8cffgaiwefihsilTGN-L-siRNA-IITGN-ECL-SEQ ID NO: 1802 (D)0.25364.0gffgaiwefihsilTGN-L-siRNA-IITGN-ECL-SEQ ID NO: 1802 (D)0.25128.7gffgaiwefihsil

Claims

1. (1) A first composition comprising an oligonucleotide (R) linked to a targeting ligand (G) via a linker (L); and (2) a second composition comprising a peptide (P) linked to a targeting ligand (G) via a linker (L); wherein (R)-(L)-(G) and (P)-(L)-(G) are selected from the following table: Entry(R)-(L)-(G)(P)-(L)-(G)1TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)2TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1643 (D)3TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1078 (D)4TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1662 (D)5TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1696 (D)6TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1657 (D)7TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1660 (D)8TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)9TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1653 (D)10TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1652 (D)11TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1651 (D)12TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1650 (D)13TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1649 (D)14TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1648 (D)15TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1647 (D)16TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)17TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1645 (D)18TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1633 (D)19TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1632 (D)20TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1634 (D)21TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1631 (D)22TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1697 (D)23TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1702(D)24TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1703 (D)25TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1704 (D)26TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1705 (D)27TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1706 (D)28TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1707 (D)29TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1708 (L)30TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1711 (L)31TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1712 (L)32TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1716 (L)33TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1719 (L)34TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1403 (L)35TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1517 (L)36TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 935 (L)37TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1720 (L)38TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1725 (L)39TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1726 (D)40TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1727 (D)41TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1728(D)42TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1730 (D)43TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1731(D)44TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1733 (D)45TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1734 (D)46TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)47TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)48TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1744 (D)49TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)50TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)51TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)52TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)53TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)54TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)55TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)56TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D) wherein TGN-L-siRNA is SiRNA-II is SiRNA comprising SEQ ID Nos. 1803 and 1805 and SiRNA-III is SiRNA comprising SEQ ID Nos. 1803 and 1806; and TGN-S-S-peptide SEQ ID NO. is: for use as a medicament, wherein the first composition comprising (R)-(L)-(G) and the second composition comprising (P)-(L)-(G) are sequentially administered about 6 minutes to 1 hour apart.

2. An in vitro or ex vivo method for inhibiting expression of a gene comprising administering: (1) a first composition comprising an oligonucleotide (R) linked to a targeting ligand (G) via a linker (L); and (2) a second composition comprising a peptide (P) linked to a targeting ligand (G) via a linker (L); wherein (R)-(L)-(G) and (P)-(L)-(G) are selected from the following table: Entry(R)-(L)-(G)(P)-(L)-(G)1TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1710 (D)2TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1643 (D)3TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1078 (D)4TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1662 (D)5TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1696 (D)6TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1657 (D)7TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1660 (D)8TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1654 (D)9TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1653 (D)10TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1652 (D)11TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1651 (D)12TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1650 (D)13TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1649 (D)14TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1648 (D)15TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1647 (D)16TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1701 (D)17TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1645 (D)18TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1633 (D)19TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1632 (D)20TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1634 (D)21TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1631 (D)22TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1697 (D)23TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1702(D)24TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1703 (D)25TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1704 (D)26TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1705 (D)27TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1706 (D)28TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1707 (D)29TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1708 (L)30TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1711 (L)31TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1712 (L)32TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1716 (L)33TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1719 (L)34TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1403 (L)35TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1517 (L)36TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 935 (L)37TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1720 (L)38TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1725 (L)39TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1726 (D)40TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1727 (D)41TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1728(D)42TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1730 (D)43TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1731(D)44TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1733 (D)45TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1734 (D)46TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1733(D)47TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1709 (D)48TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1744 (D)49TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1745 (D)50TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1419 (D)51TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 1248 (D)52TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 26 (D)53TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 74 (D)54TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 82 (D)55TGN-L-siRNA-IIITGN-S-S-SEQ ID NO: 543 (D)56TGN-L-siRNA-IITGN-S-S-SEQ ID NO: 1709 (D) wherein TGN-L-siRNA is TGN-S-S-peptide SEQ ID NO. is: SiRNA-II is SiRNA comprising SEQ ID Nos. 1803 and 1805 and SiRNA-III is SiRNA comprising SEQ ID Nos. 1803 and 1806; wherein the first composition comprising R-(L)-(G) and the second composition comprising (P)-(L)-(G) are sequentially administered about 6 minutes to 1 hour apart.

3. The method of any preceding claim or the composition for use according to any preceding claim, wherein the oligonucleotide is administered at a dose of 0.1 to 5 mpk; and the peptide is administered at a dose of 1 to 100 mpk .