Glucagon-like peptide-1-t3 conjugates
AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. DIMARCHI, Brian FINAN, Bin YANG, Zhimeng ZHU
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Abstract
Provided herein are GLP-1 agonist peptides conjugated with thyroid hormone receptor ligands that are capable of acting at the thyroid hormone receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes, obesity, metabolic syndrome and chronic cardiovascular disease, comprising administering the conjugates of the invention.
Claims29
A conjugate comprising the structure Q-L-Y;
- wherein
- Q is a GLP-1 agonist peptide comprising
- A) the sequence
- (SEQ ID NO:
- 43)
- X1X2X3GTFTSDVSX12YLX15X16QAAX20X21FIX24WLX27X28X29
- wherein
- X1 is selected from the group consisting of His, D-His, N-methyl-His, alpha-methyl-His, imidazole acetic acid, des-amino-His, hydroxyl-His, acetyl-His, homo-His, or alpha, alpha-dimethyl imidiazole acetic acid (DMIA);
- X2 is selected from the group consisting of Ser, D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, Aib, Val, or α-amino-N-butyric acid;
- X3 is glutamic acid, ornithine, norleucine;
- X12 is Lys or Arg;
- X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid;
- X16 is Aib, glutamic acid, glutamine, homoglutamic acid, homocysteic acid, threonine or glycine;
- X20 is Glu, Lys or Aib;
- X21 is Glu or Aib;
- X24 is Ala, Glu, Lys or Aib;
- X27 is Met, Val, Leu or Nle;
- X28 is Glu, Lys or Aib;
- and
- X29 is Gly, Gln, Asp or Glu;
- or
- B) the sequence
- (SEQ ID NO:
- 37)
- X1X2EGTFTSDVSSYLX15X16QAAX20X21FIX24WLX27KG
- wherein
- X1 is selected from the group consisting of His, D-His, N-methyl-His, alpha-methyl-His, imidazole acetic acid, des-amino-His, hydroxyl-His, acetyl-His, homo-His, or alpha, alpha-dimethyl imidiazole acetic acid (DMIA);
- X2 is selected from the group consisting of Ser, D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, Aib, Val, or α-amino-N-butyric acid;
- X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid;
- X16 is Gly, Glu, Lys or Aib,
- X20 is Glu, Ala, Lys or Aib;
- X21 is Glu or Aib;
- X24 is Ala, Glu, Lys or Aib;
- X27 is Met, Val, Leu or Nle;
- Y is a thyroid receptor ligand having the general structure of:
- I)
- wherein
- R15 is C1-C4 alkyl, —CH2(pyridazinone), —CH2(OH)(phenyl)F, —CH(OH)CH3, halo or H;
- R20 is halo, CH3 or H—;
- R21 is halo, CH3 or H—;
- R22 is H, OH, halo, —CH2(OH)(C6 aryl)F, or C1-C4 alkyl;
- and
- R23 is —CH2CH(NH2)COOH, —OCH2COOH, —NHC(O)COOH, —CH2COOH, —NHC(O)CH2COOH, —CH2CH2COOH, and —OCH2PO32−;
- or
- II)
- wherein
- R20, R21 and R22 are independently selected from the group consisting of H, OH, halo and C1-C4 alkyl;
- and
- R15 is halo or H;
- or
- III)
- wherein
- R15 is isopropyl;
- R20 is CH3;
- R21 is CH3;
- R22 is H;
- and
- R23 is —OCH2PO32;
- and
- L is a linking group or a bond joining Q to Y.
2-4. (canceled)
7-11. (canceled)
(canceled)
(canceled)
23-27. (canceled)
A conjugate comprising the structure Q-L-Y;
- wherein
- Q is a GLP-1 agonist peptide comprising the sequence
- (SEQ ID NO:
- 37)
- X1X2EGTFTSDVSSYLX15X16QAAX20X21FIX24WLX27KGGPSSGAPPPSK;
- or
- (SEQ ID NO:
- 49)
- H(aib)EGTFTSDVSSYLEEQAAKEFIAWLVKGGPSSGAPPPSK-amide
- wherein
- X1 is selected from the group consisting of His, D-His, N-methyl-His, alpha-methyl-His, imidazole acetic acid, des-amino-His, hydroxyl-His, acetyl-His, homo-His, or alpha, alpha-dimethyl imidiazole acetic acid (DMIA);
- X2 is selected from the group consisting of Ser, D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, Aib, Val, or α-amino-N-butyric acid;
- X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid;
- X16 is Gly, Glu, Lys or Aib,
- X20 is Glu, Ala, Lys or Aib;
- X21 is Glu or Aib;
- X24 is Ala, Glu, Lys or Aib;
- and
- X27 is Met, Val, Leu or Nle;
- and wherein L-Y comprises the structure
- and
- L-Y is conjugated to an amino acid side chain of the GLP-1 agonist peptide at position 40.
31-32. (canceled)
(canceled)
36-37. (canceled)
39-42. (canceled)
Dependencies are inferred from the claim text.