IP Library › Granted Patent US 10,577,405

Granted Patent B2

US 10,577,405 · App. 15/820,127 · Granted Mar 3, 2020

Peptide pharmaceuticals for insulin resistance

Inventor: John J. Nestor (Sugar Land, TX)

Assignee: Mederis Diabetes LLC

C07K14/605 A61K38/26 A61K47/549 A61K47/64 A61K38/00

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Quick Facts

Patent No.: US 10,577,405
App. No.: 15/820,127
Granted: Mar 3, 2020
Kind: B2

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Abstract

Described herein are methods of syntheses and therapeutic uses of covalently modified peptides and/or proteins. The covalently modified peptides and/or proteins allow for improved pharmaceutical properties of peptide and protein-based therapeutics.

Claims (114)

1. A method of treating obesity, metabolic syndrome, insulin resistance, diabetes or cardiovascular disease, or a condition associated with obesity, metabolic syndrome, insulin resistance, diabetes or cardiovascular disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a peptide product selected from the group consisting of:

(SEQ. ID. NO. 819)

1) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -

Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 820)

2) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys * 20 -Glu 21 -Phe 22 -Ile 23 -

Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 821)

3) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-octadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -

Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1114)

4) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-dodecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -

Lys(N-omega(1-dodecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1115)

5) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -

Lys(N-omega(1-tetradecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1116)

6) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -

Lys(N-omega(1-hexadecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1117)

7) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -

Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1118)

8) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -

Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1119)

9) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -

Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1120)

10) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-

D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1121)

11) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy)

beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1122)

12) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -

Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy)

beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1102, EU-A1865)

13) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -

Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1103, EU-A1866)

14) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -

Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1104, EU-A1867)

15) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -

Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1105, EU-A1868)

16) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-

glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

(SEQ. ID. NO. 1106, EU-A1869)

17) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-

D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

and

(SEQ. ID. NO. 1107, EU-A1870)

18) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -

Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-

D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 ;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the obesity, metabolic syndrome, insulin resistance, diabetes or cardiovascular disease, or the condition associated with obesity, metabolic syndrome, insulin resistance, diabetes or cardiovascular disease, is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, elevated blood levels of free fatty acids or glycerol, hyperglycemia, hypertension, syndrome X, prediabetes, type 1 diabetes, type 2 diabetes, gestational diabetes, diabetic complications, hyperinsulinemia, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, atherosclerosis, acute cardiovascular syndrome, coronary artery disease, infarction, myocardial infarction, stroke, peripheral vascular disease, ischemia-reperfusion injury, impairments in wound healing, systemic inflammation, and musculoskeletal diseases.

3. The method of claim 1 , wherein the peptide product induces weight loss.

4. The method of claim 1 , wherein the peptide product is administered parenterally.

5. The method of claim 4 , wherein the peptide product is administered subcutaneously, intravenously or intramuscularly.

6. The method of claim 1 , wherein the peptide product is administered transmucosally.

7. The method of claim 6 , wherein the peptide product is administered intranasally or by inhalation.

8. The method of claim 1 , wherein the peptide product is administered once weekly or twice weekly.

9. The method of claim 1 , wherein the peptide product is:

His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1119), or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the peptide product is:

His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1121), or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the peptide product is:

His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1122), or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , further comprising administering at least one additional therapeutic agent.

13. The method of claim 12 , wherein the at least one additional therapeutic agent is selected from the group consisting of anti-obesity agents, lipid-lowering agents, pro-satiety agents, anti-hypertensive agents, antidiabetic agents, anti-atherosclerotic agents and anti-inflammatory agents.

14. A method of producing a peptide product selected from the group consisting of:

1) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 819);

2) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 820);

3) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-octadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 821);

4) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-dodecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-dodecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1114);

5) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-tetradecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-tetradecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1115);

6) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-hexadecyl alpha-D-melibiouronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-hexadecyl beta-D-glucouronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1116);

7) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1117);

8) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1118);

9) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1119);

10) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1120);

11) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1121);

12) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Tyr 10 -Ser 11 -Lys 12 -Tyr 13 -Leu 14 -Asp 15 -Glu* 16 -Gln 17 -Ala 18 -Ala 19 -Lys* 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1122);

13) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1102, EU-A1865);

14) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1103, EU-A1866);

15) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Gln 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1104, EU-A1867);

16) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(13-carboxyl-tridecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1105, EU-A1868);

17) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(15-carboxyl-pentadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1106, EU-A1869); and

18) His 1 -Aib 2 -Gln 3 -Gly 4 -Thr 5 -Phe 6 -Thr 7 -Ser 8 -Asp 9 -Glu* 10 -Ser 11 -Lys 12 -Tyr 13 -Lys* 14 -Asp 15 -Ser 16 -Gln 17 -Ala 18 -Ala 19 -Gln 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega(1-(17-carboxyl-heptadecyloxy) beta-D-glucuronyl)) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -Thr 29 -NH 2 (SEQ. ID. NO. 1107, EU-A1870);

or a pharmaceutically acceptable salt thereof, comprising:

conjugating a surfactant intermediate to a protected peptide intermediate; and

deprotecting the peptide.

15. The method claim 14 , wherein the surfactant intermediate is protected, and the method further comprises deprotecting the surfactant after conjugation of the protected surfactant intermediate to the protected peptide intermediate.

16. The method claim 14 , further comprising removing the peptide-surfactant conjugate from a solid support.

Assignments (4)

SECURITY INTEREST Recorded May 14, 2025

From: ALTIMMUNE, INC.; SPITFIRE PHARMA, LLC

To: HERCULES CAPITAL, INC., AS AGENT

Reel/Frame 071108/0692 →

AFFIDAVIT OF ADDRESS CHANGE Recorded Feb 19, 2025

From: MEDERIS DIABETES, LLC

To: MEDERIS DIABETES LLC

Reel/Frame 070266/0875 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 20, 2019

From: SPITFIRE PHARMA INC.