US2019134214A1PendingUtilityA1
GLP-1 Receptor Ligand Moiety Conjugated Oligonucleotides and Uses Thereof
Est. expiryMay 6, 2036(~9.8 yrs left)· nominal 20-yr term from priority
Inventors:Brett P. MoniaThazha P. PrakashGarth A. KinbergerRichard E. LeePunit P. SethShalini AnderssonEva Carina ÄmmäläDaniel Laurent KnerrMaria Astrid Ölwegård-HalvarssonEric ValeurWilliam John Drury Iii
A61P 43/00A61P 3/08A61P 35/00A61K 38/1796C12N 2320/32C12N 2310/3341C12N 2310/3231C12N 2310/315C12N 2310/3521C12N 2310/321A61K 31/7125C12N 15/111C12N 2310/11A61K 47/65A61K 31/713C12N 2310/3513C12N 2310/322C12N 2310/3533C12N 2310/3525A61K 47/549A61K 47/6425C07K 19/00C07K 14/605C12N 15/113
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Claims
Abstract
The present embodiments provide compounds and methods for targeting cells expressing GLP-1 receptor.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound comprising a modified oligonucleotide, conjugate linker, and GLP-1 receptor ligand conjugate moiety.
2 . The compound of claim 1 , wherein the conjugate linker links the modified oligonucleotide to the GLP-1 receptor ligand conjugate moiety.
3 . The compound of claim 1 or 2 , wherein the modified oligonucleotide is 8 to 80 linked nucleosides in length.
4 . The compound of claim 3 , wherein the modified oligonucleotide is 10 to 30 linked nucleosides in length.
5 . The compound of claim 3 , wherein the modified oligonucleotide is 12 to 30 linked nucleosides in length.
6 . The compound of claim 3 , wherein the modified oligonucleotide is 15 to 30 linked nucleosides in length.
7 . The compound of any of claims 1 - 6 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.
8 . The compound of claim 7 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
9 . The compound of claim 8 , wherein each modified internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.
10 . The compound of any of claims 7 - 9 , wherein the modified sugar is a bicyclic sugar.
11 . The compound of claim 10 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt).
12 . The compound of any of claims 7 - 9 , wherein the modified sugar is 2′-O-methoxyethyl, 2′-F, or 2′-OMe.
13 . The compound of any of claims 7 - 12 , wherein the modified nucleobase is a 5-methylcytosine.
14 . The compound of any of claims 1 - 13 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
15 . The compound of any of claims 1 - 14 , wherein the modified oligonucleotide is single-stranded.
16 . The compound of claim 15 , wherein the modified oligonucleotide is an antisense oligonucleotide.
17 . The compound of claim 15 , wherein the modified oligonucleotide is a miRNA antagonist or miRNA mimic.
18 . The compound of any of claims 1 - 14 , wherein the compound comprises a double-stranded duplex.
19 . The compound of claim 18 , wherein the double-stranded duplex comprises:
a first strand comprising the modified oligonucleotide; and a second strand complementary to the first strand.
20 . The compound of claim 19 , wherein the first strand comprising the modified oligonucleotide is complementary to a RNA transcript.
21 . The compound of claim 19 , wherein the second strand is complementary to a RNA transcript.
22 . The compound of claim 18 , wherein the compound is a miRNA mimic.
23 . The compound of any of claims 1 - 22 , wherein the compound comprises ribonucleotides.
24 . The compound of any of claims 1 - 22 , wherein the compound comprises deoxyribonucleotides.
25 . The compound of any of claims 1 - 24 , wherein the modified oligonucleotide is complementary to a RNA transcript in a cell.
26 . The compound of claim 25 , wherein the cell is a pancreatic cell.
27 . The compound of claim 26 , wherein the pancreatic cell is a beta-islet cell.
28 . The compound of any of claims 25 - 27 , wherein the RNA transcript is pre-mRNA, mRNA, non-coding RNA, or miRNA.
29 . The compound of any of claims 1 - 28 , wherein the GLP-1 receptor ligand conjugate moiety is a peptide conjugate moiety, small molecule conjugate moiety, aptamer conjugate moiety, or antibody conjugate moiety targeted to GLP-1 receptor.
30 . The compound of claim 29 , wherein the peptide conjugate moiety is a GLP-1 peptide conjugate moiety.
31 . The compound of claim 30 , wherein the GLP-1 peptide conjugate moiety comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 contiguous amino acid portion at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% homologous to an equal length portion of the amino acid sequence of any of SEQ ID NOs: 1-57.
32 . The compound of claim 31 , wherein the GLP-1 peptide conjugate moiety comprises a conservative amino acid substitution, an amino acid analog, or an amino acid derivative, wherein the conservative amino acid substitution comprises replacement of an aliphatic amino acid with another aliphatic amino acid; replacement of a serine with a threonine or vice versa; replacement of an acidic residue with another acidic residue; replacement of a residue bearing an amide group with another residue bearing an amide group; exchange of a basic residue with another basic residue; or, replacement of an aromatic residue with another aromatic residue, or a combination thereof, and the aliphatic residue comprises Alanine, Valine, Leucine, Isoleucine or a synthetic equivalent thereof; the acidic residue comprises Aspartic acid, Glutamic acid or a synthetic equivalent thereof, the residue comprising an amide group comprises Aspartic acid, Glutamic acid or a synthetic equivalent thereof; the basic residue comprises Lysine, Arginine or a synthetic equivalent thereof, or, the aromatic residue comprises Phenylalanine, Tyrosine or a synthetic equivalent thereof.
33 . The compound of claim 31 , wherein the GLP-1 peptide conjugate moiety comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 contiguous amino acid portion at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to an equal length portion of the amino acid sequence of any of SEQ ID NOs: 1-57.
34 . The compound of claim 30 , wherein the GLP-1 peptide conjugate moiety is 8 to 50 amino acids in length and is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% homologous over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.
35 . The compound of claim 34 , wherein the GLP-1 peptide conjugate moiety comprises a conservative amino acid substitution, an amino acid analog, or an amino acid derivative.
36 . The compound of claim 34 , wherein the GLP-1 peptide conjugate moiety is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.
37 . The compound of any of claims 30 - 36 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence of any of SEQ ID NOs: 1-57.
38 . The compound of claim 37 , wherein the GLP-1 peptide conjugate moiety consists of the amino acid sequence of any of SEQ ID NOs: 1-57.
39 . The compound of any of claims 30 - 36 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.
40 . The compound of claim 39 , wherein the GLP-1 peptide conjugate moiety consists of the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.
41 . The compound of any of claims 30 - 36 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.
42 . The compound of claim 41 , wherein the GLP-1 peptide conjugate moiety consists of the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.
43 . The compound of any of claims 30 - 36 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 1).
44 . The compound of claim 43 , wherein the GLP-1 peptide conjugate moiety consists of the amino acid sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 1).
45 . The compound of any of claims 30 - 44 , wherein the GLP-1 peptide conjugate moiety is capable of binding to GLP-1 receptor.
46 . The compound of claim 45 , wherein the GLP-1 receptor is expressed on the surface of a cell.
47 . The compound of claim 46 , wherein the cell is a pancreatic cell.
48 . The compound of claim 47 , wherein the pancreatic cell is a beta-islet cell.
49 . The compound of any of claims 46 - 48 , wherein the cell is in an animal.
50 . The compound of any of claims 1 - 49 , wherein the compound comprises at least one, at least two, at least three, at least four, or at least five GLP-1 receptor ligand conjugate moieties.
51 . The compound of any of claims 1 - 50 , wherein the conjugate linker links the GLP-1 receptor ligand conjugate moiety to the 5′ end of the modified oligonucleotide.
52 . The compound of any of claims 1 - 50 , wherein the conjugate linker links the GLP-1 receptor ligand conjugate moiety to the 3′ end of the modified oligonucleotide.
53 . The compound of any of claims 1 - 52 , wherein the conjugate linker is cleavable.
54 . The compound of any of claims 1 - 53 , wherein the conjugate linker comprises a disulfide linkage.
55 . The compound of claim 54 , wherein the disulfide linkage comprises penicillamine.
56 . The compound of claim 55 , wherein the GLP-1 receptor ligand conjugate moiety is the GLP-1 peptide conjugate moiety of any of claims 30 - 44 and the disulfide linkage links the GLP-1 peptide conjugate moiety to the modified oligonucleotide.
57 . The compound of claim 56 , wherein the disulfide linkage links the C-terminus of the GLP-1 peptide conjugate moiety to the 5′end or 3′ end of the modified oligonucleotide.
58 . The compound of any of claims 1 - 57 , wherein the conjugate linker comprises 1-5 linker-nucleosides.
59 . The compound of claim 58 , wherein the conjugate linker comprises 3 linker-nucleosides.
60 . The compound of claim 59 , wherein the 3 linker-nucleosides have a TCA motif.
61 . The compound of claim 58 , wherein 1-5 linker-nucleosides do not comprise a TCA motif.
62 . The compound of any of claims 1 - 61 , wherein the conjugate linker comprises a hexylamino group.
63 . The compound of any of claims 1 - 62 , wherein the conjugate linker comprises a polyethylene glycol group.
64 . The compound of any of claims 1 - 63 , wherein the conjugate linker comprises a triethylene glycol group.
65 . The compound of any of claims 1 - 64 , wherein the conjugate linker comprises a phosphate group.
66 . The compound of any of claims 1 - 65 , wherein the conjugate linker comprises:
wherein
X directly or indirectly attaches to the GLP-1 receptor ligand conjugate moiety; and
Y directly or indirectly attaches to the modified oligonucleotide.
67 . The compound of claim 66 , wherein X comprises O.
68 . The compound of claim 66 or 67 , wherein Y comprises a phosphate group.
69 . The compound of any of claims 66 - 68 , wherein X attaches to the GLP-1 receptor ligand conjugate moiety by the disulfide linkage of any of claims 54 - 57 .
70 . The compound of any of claims 1 - 69 , wherein the conjugate linker comprises:
wherein X directly or indirectly attaches to the GLP-1 receptor ligand conjugate moiety; and
wherein T 1 comprises the modified oligonucleotide; and Bx is a modified or unmodified nucleobase.
71 . The compound of claim 70 , wherein X comprises the disulfide linkage of any of claims 54 - 57 .
72 . The compound of any of claims 1 - 71 , wherein the conjugate linker comprises:
wherein:
the phosphate group is connected to the modified oligonucleotide and Y is connected to the conjugate group;
Y is a phosphodiester or amino (—NH—) group;
Z is a pyrrolidinyl group having the formula:
j is 0 or 1;
n is from about 1 to about 10;
p is from 1 to about 10;
m is 0 or from 1 to 4; and
when Y is amino then m is 1.
73 . The compound of claim 72 , wherein Y is amino (—NH—).
74 . The compound of claim 72 , wherein Y is a phosphodiester group.
75 . The compound of any of claims 72 to 74 , wherein n is 3 and p is 3.
76 . The compound of any of claims 72 to 74 , wherein n is 6 and p is 6.
77 . The compound of any of claims 72 to 74 , wherein n is from 2 to 10 and p is from 2 to 10.
78 . The compound of any of claims 72 to 74 , wherein n and p are different.
79 . The compound of any of claims 72 to 74 , wherein n and p are the same.
80 . The compound of any of claims 72 and 74 to 79 , wherein m is 0.
81 . The compound of any of claims 72 to 79 , wherein m is 1.
82 . The compound of any of claims 72 to 81 , wherein j is 0.
83 . The compound of any of claims 72 to 81 , wherein j is 1 and Z has the formula:
84 . The compound of claim 83 , wherein n is 2 and p is 3.
85 . The compound of claim 83 , wherein n is 5 and p is 6.
86 . The compound of any of claims 1 - 85 , wherein the conjugate linker comprises:
87 . The compound of any of claims 1 - 85 , wherein the conjugate linker comprises:
88 . The compound of any of claims 1 - 85 , wherein the compound comprising the conjugate linker comprises:
wherein
N—N═N represents an azido group of the GLP-1 receptor ligand conjugate moiety and X directly or indirectly attaches to the remainder of the GLP-1 receptor ligand conjugate moiety; and
Y directly or indirectly attaches to the oligonucleotide.
89 . The compound of any of claims 1 - 85 , wherein the compound comprising the conjugate linker comprises:
wherein
N—N═N represents an azido group of the GLP-1 receptor ligand conjugate moiety and X directly or indirectly attaches to the remainder of the GLP-1 receptor ligand conjugate moiety; and
Y directly or indirectly attaches to the oligonucleotide.
90 . The compound of any of claims 1 - 85 , wherein the compound comprising the conjugate linker comprises:
wherein
N—N═N represents an azido group of the GLP-1 receptor ligand conjugate moiety and X directly or indirectly attaches to the remainder of the GLP-1 receptor ligand conjugate moiety; and
Y directly or indirectly attaches to the oligonucleotide.
91 . A method of modulating the expression of a nucleic acid target in a cell comprising contacting the cell with the compound of any of claims 1 to 90 , thereby modulating expression of the nucleic acid target in the cell.
92 . The method of claim 91 , wherein the cell is a pancreatic cell.
93 . The method of claim 92 , wherein the pancreatic cell is a beta-islet cell.
94 . The method of any of claims 91 - 93 , wherein the cell expresses GLP-1 receptor on the surface of the cell.
95 . The method of any of claims 91 - 94 , wherein contacting the cell with the compound inhibits expression of the nucleic acid target.
96 . The method of any of claims 91 - 95 , wherein the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA.
97 . The method of any of claims 91 - 96 , wherein the cell is in an animal.
98 . A method of preparing a compound, the method comprising reacting:
with a GLP-1 peptide; wherein X 1 is an oligonucleotide and the compound is a GLP-1 peptide conjugated oligonucleotide.
99 . A method of preparing a GLP-1 peptide conjugated oligonucleotide, the method comprising:
reacting an oligonucleotide comprising a hexamethyl linker and a terminal amine at the 5′ end of the oligonucleotide with 3-(2-Pyridyldithio propionic acid N-hydroxysuccinimide ester) having the formula:
thereby yielding Compound 2 having the formula:
wherein X 1 is the oligonucleotide; and
reacting Compound 2 with GLP-1 peptide, thereby yielding the GLP-1 peptide conjugated oligonucleotide having the formula:
wherein X 1 is the oligonucleotide and X 2 is the GLP-1 peptide.
100 . A method of preparing a GLP-1 peptide conjugated oligonucleotide, the method comprising:
mixing a solution comprising an oligonucleotide comprising a hexamethyl linker and a terminal amine at the 5′ end of the oligonucleotide with a solution comprising 3-(2-Pyridyldithio propionic acid N-hydroxysuccinimide ester) having the formula:
thereby yielding Compound 2 having the formula:
wherein X 1 is the oligonucleotide; and
mixing a solution comprising Compound 2 with a solution comprising GLP-1 peptide, thereby yielding the GLP-1 peptide conjugated oligonucleotide having the formula:
wherein X 1 is the oligonucleotide and X 2 is the GLP-1 peptide.
101 . The method of claim 100 , wherein the solution comprising the oligonucleotide comprises sodium phosphate buffer and the solution comprising 3-(2-Pyridyldithio propionic acid N-hydroxysuccinimide ester) comprises dimethylformamide.
102 . The method of claim 100 or 101 , wherein the solutions are mixed at room temperature.
103 . The method of any of claims 100 - 102 , wherein the solution comprising Compound 2 further comprises acetonitrile and NaHCO 3 and has a pH of about 8.0.
104 . The method of any of claims 100 - 103 , wherein the solution comprising GLP-1 peptide further comprises dimethylformamide.
105 . The method of any of claims 98 - 104 , wherein the GLP-1 peptide comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 contiguous amino acid portion at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% homologous to an equal length portion of the amino acid sequence of any of SEQ ID NOs: 1-57.
106 . The method of claim 105 , wherein the GLP-1 peptide comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 contiguous amino acid portion at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to an equal length portion of the amino acid sequence of any of SEQ ID NOs: 1-57.
107 . The method of any of claims 98 - 104 , wherein the GLP-1 peptide is 8 to 50 amino acids in length and is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% homologous over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.
108 . The method of claim 107 , wherein the GLP-1 peptide is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.
109 . The method of any of claims 105 - 108 , wherein the GLP-1 peptide comprises the amino acid sequence of GLP-1(7-37) (SEQ ID NO: 1).
110 . The method of claim 109 , wherein the GLP-1 peptide consists of the amino acid sequence of GLP-1(7-37) (SEQ ID NO: 1).
111 . The method of any of claims 105 - 108 , wherein the GLP-1 peptide comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.
112 . The method of claim 111 , wherein the GLP-1 peptide consists of the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.
113 . The method of any of claims 105 - 108 , wherein the GLP-1 peptide comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.
114 . The method of claim 113 , wherein the GLP-1 peptide consists of the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.
115 . The method of any of claims 105 - 108 , wherein the GLP-1 peptide comprises the amino acid sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 1).
116 . The method of claim 115 , wherein the GLP-1 peptide consists of the amino acid sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 1).
117 . The method of any of claims 105 - 116 , wherein the GLP-1 peptide moiety comprises a reactive sulfur moiety.
118 . The method of any of claims 105 - 117 , wherein the GLP-1 peptide comprises penicillamine.
119 . The method of claim 118 , wherein the penicillamine is linked to the C-terminus of the GLP-1 peptide.
120 . A pharmaceutical composition comprising at least one compound of any one of claims 1 to 90 and a pharmaceutically acceptable excipient.
121 . The compound of any of claims 30 - 36 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Zaa (SEQ ID NO: 56).Join the waitlist — get patent alerts
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