IP Library › Granted Patent US 11,065,304

Granted Patent B2

US 11,065,304 · App. 14/646,264 · Granted Jul 20, 2021

Peptide pharmaceuticals for insulin resistance

Inventor: John J. Nestor (Encinitas, CA)

Assignee: Mederis Diabetes, LLC

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

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,065,304
App. No.: 14/646,264
Granted: Jul 20, 2021
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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 (329)

1. A peptide product comprising a surfactant X covalently attached to a peptide, the peptide comprising a linker amino acid U and at least one other amino acid:

wherein the surfactant X is a group of Formula I:

wherein:

R 1a is independently, at each occurrence, selected from the group consisting of a bond, H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, and a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, selected from the group consisting of a protecting group, a saccharide, a bond, H, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, and a substituted or unsubstituted aralkyl group;

W 1 is independently, at each occurrence, selected from the group consisting of —CH 2 —, —CH 2 —O—, —(C═O), —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C═S)—NH—, and —CH 2 —S—;

W 2 is selected from the group consisting of —O—, —CH 2 — and —S—;

R 2 is a bond to U; and,

n is 1, 2 or 3;

the peptide is of Formula II:

Formula II

(SEQ. ID. NO. 1)

aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -aa 12 -

aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -aa 21 -aa 22 -

aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -aa 30 -aa 31 -aa 32 -

aa 33 -aa 34 -aa 35 -aa 36 -aa 37 -Z

wherein:

Z is selected from the group consisting of OH, N—R 4 -His, and —NH—R 3 , wherein

R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 12 alkyl, and a PEG chain of less than 10 Da;

R 4 is a C 2 -C 10 acyl group;

aa 1 is selected from the group consisting of His, N—R 4 -His, pGlu-His, and N—R 3 -His;

aa 2 is selected from the group consisting of Ser, D-Ser, Ala, Gly, Pro, MePro, Aib, Ac4c, and Ac5c;

aa 3 is selected from the group consisting of Gln and Cit;

aa 4 is selected from the group consisting of Gly and D-Ala;

aa 5 is selected from the group consisting of Thr and Ser;

aa 6 is selected from the group consisting of Phe, Trp, 2FPhe, MePhe, 2FMePhe, and Nal2;

aa 7 is selected from the group consisting of Thr and Ser;

aa 8 is selected from the group consisting of Ser and Asp;

aa 9 is selected from the group consisting of Asp and Glu;

aa 10 is selected from the group consisting of Tyr, Feu, Met, Nal2, Bip, Bip2EtMeO, and U;

aa 11 is absent or selected from the group consisting of Ser, Asn, Bip, and U;

aa 12 is absent or selected from the group consisting of Lys, Glu, Ser, Arg, and U;

aa 13 is absent or selected from the group consisting of Tyr, Gln, Cit, and U;

aa 14 is absent or selected from the group consisting of Leu, Met, Nle, and U;

aa 15 is absent or selected from the group consisting of Asp, Glu, and U;

aa 16 is absent or selected from the group consisting of Ser, Gly, Glu, Ala, Aib, Ac5c, Lys, Arg, and U;

aa 17 is absent or selected from the group consisting of Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, Lys, and U;

aa 18 is absent or selected from the group consisting of Arg, hArg, Ala, Aib, Ac4c, Ac5c, and U;

aa 19 is absent or selected from the group consisting of Ala, Val, Aib, Ac4c, Ac5c, and U;

aa 20 is absent or selected from the group consisting of Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, and U;

aa 21 is absent or selected from the group consisting of Asp, Glu, Leu, Aib, Ac4c, Ac5c, and U;

aa 22 is absent or selected from the group consisting of Phe, Trp, Nal2, Aib, Ac4c, Ac5c, and U;

aa 23 is absent or selected from the group consisting of Val, lle, Aib, Ac4c, Ac5c, and U;

aa 24 is absent or selected from the group consisting of Gln, Ala, Glu, Cit, and U;

aa 25 is absent or selected from the group consisting of Trp, Nal2, and U;

aa 26 is absent or selected from the group consisting of Leu and U;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is absent or selected from the group consisting of Thr, Gly, Aib, Ac4c, Ac5c, and U;

aa 30 is absent or selected from the group consisting of Lys, Aib, Ac4c, Ac5c, Arg, and U;

aa 31 is absent or selected from the group consisting of Arg, Aib, Ac4c, Ac5c, and U;

aa 32 is absent or selected from the group consisting of Asn, Aib, Ac4c, Ac5c, and U;

aa 33 is absent or selected from the group consisting of Arg, Aib, Ac4c, Ac5c, and U;

aa 34 is absent or selected from the group consisting of Asn, Aib, Ac4c, Ac5c, and U;

aa 35 is absent or selected from the group consisting of Asn, Aib, Ac4c, Ac5c, and U;

aa 36 is absent or selected from the group consisting of Ala, lle, Aib, Ac4c, Ac5C, and U;

aa 37 is absent or U;

U is a natural or unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X;

wherein any two of aa 1 -aa 37 are optionally cyclized through their side chains to form a lactam linkage; and

provided that one, or at least one, of aa 10 -aa 26 or aa 29 -aa 37 is the linker amino acid U covalently attached to X.

2. The peptide product of claim 1 , wherein X has the structure:

wherein:

R 1a is selected from the group consisting of H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, and a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, selected from the group consisting of H, a protecting group, a saccharide, and a substituted or unsubstituted C 1 -C 30 alkyl group;

W 2 is selected from the group consisting of —O— and —S—; and

R 2 is a bond to U.

3. The peptide product of claim 2 , wherein X has the structure:

wherein:

1) R 1a is selected from the group consisting of H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, and a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, selected from the group consisting of H, a protecting group, and a substituted or unsubstituted C 1 -C 30 alkyl group;

W 1 is —(C═O)—NH—;

W 2 is —O—; and

R 2 is a bond to U; or

2) R 1a is a substituted or unsubstituted C 1 -C 30 alkyl group;

R 1b , R 1c , and R 1d are H;

W 1 is —(C═O)—NH—;

W 2 is —O—; and

R 2 is a bond to U.

4. The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 6 -C 20 alkyl group.

5. The peptide product of claim 1 , wherein the surfactant X is a 1-alkyl glycoside class surfactant.

6. The peptide product of claim 1 , wherein X is selected from the group consisting of 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecyl beta-D-glucuronic acid, 1-dodecyl beta-D-glucuronic acid, 1-decyl beta-D-glucuronic acid, 1-octyl beta-D-glucuronic acid, 1-eicosyl beta-D-diglucuronic acid, 1-octadecyl beta-D-diglucuronic acid, 1-hexadecyl beta-D-diglucuronic acid, 1-tetradecyl beta-D-diglucuronic acid, 1-dodecyl beta-D-diglucuronic acid, 1-decyl beta-D-diglucuronic acid, 1-octyl beta-D-diglucuronic acid, or functionalized 1-eicosyl beta-D-glucose, 1-octadecyl beta-D-glucose, 1-hexadecyl beta-D-glucose, 1-tetradecyl beta-D-glucose, 1-dodecyl beta-D-glucose, 1-decyl beta-D-glucose, 1-octyl beta-D-glucose, 1-eicosyl beta-D-maltoside, 1-octadecyl beta-D-maltoside, 1-hexadecyl beta-D-maltoside, 1-tetradecyl beta-D-maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, 1-octyl beta-D-maltoside, 1-eicosyl beta-D-melibioside, 1-octadecyl beta-D-melibioside, 1-hexadecyl beta-D-melibioside, 1-tetradecyl beta-D-melibioside, 1-dodecyl beta-D-melibioside, 1-decyl beta-D-melibioside, or 1-octyl beta-D-melibioside, and the corresponding 6-carboxyl or 6,6′-dicarboxyl moiety.

7. The peptide product of claim 1 , wherein U is selected from the group consisting of Lys, Cys, Orn, Glu, and an unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X.

8. The peptide product of claim 1 , having the structure of Formula III-A:

Formula III-A

(SEQ. ID. NO. 2)

aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -aa 12 -

aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -aa 21 -aa 22 -aa 23 -

aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -Z

wherein:

Z is OH or —NH—R 3 ,

wherein R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 12 alkyl, and a PEG chain of less than 10 Da;

aa 1 is selected from the group consisting of His, N—Ac—His, pGlu-His, and N—R 3 -His;

aa 2 is selected from the group consisting of Ser, Ala, Gly, MePro, Aib, Ac4c, and Ac5c;

aa 3 is Gln or Cit;

aa 4 is Gly or D-Ala;

aa 5 is Thr or Ser;

aa 6 is selected from the group consisting of Phe, Trp, 2FPhe, MePhe, 2FMePhe, and Nal2;

aa 7 is Thr or Ser;

aa 8 is Ser or Asp;

aa 9 is Asp or Glu;

aa 10 is selected from the group consisting of Tyr, Feu, Met, Nal2, Bip, Bip2EtMeO, and U(X);

aa 11 is absent or selected from the group consisting of Ser, Asn, Bip, and U(X);

aa 12 is absent or selected from the group consisting of Fys, Glu, Ser, Arg, and U(X);

aa 13 is absent or selected from the group consisting of Tyr, Gln, Cit, and U(X);

aa 14 is absent or selected from the group consisting of Feu, Met, Nle, and U(X);

aa 15 is absent or selected from the group consisting of Asp, Glu, and U(X);

aa 16 is absent or selected from the group consisting of Ser, Gly, Glu, Ala, Aib, Ac5c, Fys, Arg, and U(X);

aa 17 is absent or selected from the group consisting of Arg, hArg, Gln, Glu, Fys, Cit, Aib, Ac4c, Ac5c, and U(X);

aa 18 is absent or selected from the group consisting of Arg, hArg, Ala, Aib, Ac4c, Ac5c, and U(X);

aa 19 is absent or selected from the group consisting of Ala, Val, Aib, Ac4c, Ac5c, and U(X);

aa 20 is absent or selected from the group consisting of Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, and U(X);

aa 21 is absent or selected from the group consisting of Asp, Glu, Leu, Aib, Ac4c, Ac5c, and U(X);

aa 22 is absent or selected from the group consisting of Phe, Trp, Nal2, Aib, Ac4c, Ac5c, and U(X);

aa 23 is absent or selected from the group consisting of Val, lie, Aib, Ac4c, Ac5c, and U(X);

aa 24 is absent or selected from the group consisting of Gln, Ala, Glu, Cit, and U(X);

aa 25 is absent or selected from the group consisting of Trp, Nal2, and U(X);

aa 26 is absent or selected from the group consisting of Leu and U(X);

aa 27 is Leu;

aa 28 is Gln; and

aa 29 is absent or selected from the group consisting of Thr, Gly, Aib, Ac4c, Ac5c, and U(X);

wherein any two of aa 1 -aa 29 are optionally cyclized through their side chains to form a lactam linkage; and

provided that one, or at least one, of aa 10 , aa 11 , aa 12 , aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , aa 24 , aa 25 , aa 26 , and aa 29 is the natural or unnatural amino acid U covalently attached to X.

9. The peptide product of claim 1 , having the structure of Formula III-B:

Formula III-B

(SEQ. ID. NO. 3)

His 1 -aa 2 -aa 3 -Gly 4 -Thr 5 -aa 6 -Thr 7 -Ser 8 -Asp 9 -aa 10 -

aa 11 -aa 12 -aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -

aa 21 -aa 22 -aa 23 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -aa 30 -Z

wherein:

Z is OH or —NH—R 3 ,

wherein R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 12 alkyl, and a PEG chain of less than 10 Da;

aa 2 is selected from the group consisting of Gly, MePro and Aib;

aa 3 is Gln or Cit;

aa 6 is selected from the group consisting of Phe, 2FPhe, MePhe, 2FMePhe, and Nal2;

aa 10 is selected from the group consisting of Tyr, Nal2, Bip, Bip2EtMeO, and U(X);

aa 11 is selected from the group consisting of absent or Ser, Asn, Bip, and U(X);

aa 12 is absent or selected from the group consisting of Lys, Glu, Ser, and U(X);

aa 13 is absent or selected from the group consisting of Tyr, Gln, Cit, and U(X);

aa 14 is absent or selected from the group consisting of Leu, Nle, and U(X);

aa 15 is absent or selected from the group consisting of Asp, Glu, and U(X);

aa 16 is absent or selected from the group consisting of Ser, Gly, Glu, Ala, Aib, Lys, Arg, and U(X);

aa 17 is absent or selected from the group consisting of Arg, hArg, Gln, Glu, Lys, Cit, Aib, and U(X);

aa 18 is absent or selected from the group consisting of Arg, hArg, Ala, Aib, Ac4c, Ac5c, and U(X);

aa 19 is absent or selected from the group consisting of Ala, Aib, and U(X);

aa 20 is absent or selected from the group consisting of Gln, Lys, Arg, Cit, Glu, Aib, and U(X);

aa 21 is absent or selected from the group consisting of Asp, Glu, Leu, Aib, and U(X);

aa 22 is absent or selected from the group consisting of Phe and U(X);

aa 23 is absent or selected from the group consisting of Val, lie, Aib and U(X);

aa 24 is absent or selected from the group consisting of Ala, Gln and U(X);

aa 25 is absent or selected from the group consisting of Trp and U(X);

aa 26 is absent or selected from the group consisting of Leu and U(X);

aa 27 is Leu;

aa 28 is Gln;

aa 29 is absent or selected from the group consisting of Thr, Aib, and U(X); and

aa 30 is absent or selected from the group consisting of Arg and U(X);

wherein any two of aa 1 -aa 23 are optionally cyclized through their side chains to form a lactam linkage; and

provided that one, or at least one, of aa 10 , aa 11 , aa 12 , aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , and aa 24 is the natural or unnatural amino acid U covalently attached to X.

10. The peptide product of claim 1 , wherein:

aa 2 is a glycine or Aib; or

aa 17 , aa 20 , or aa 24 is a lysine residue attached to X; or

the peptide comprises one or more Aib residues.

11. The peptide product of claim 1 having the structure:

(SEQ. ID. NO. 774)

His 1 -aa 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 -aa 16 -aa 17 -Ala 18 -Ala 19 -

aa 20 -Glu 21 -Phe 22 -aa 23 -aa 24 -Trp 25 -Leu 26 -aa 27 -aa 28 -

Thr 29 -NH 2 ;

wherein:

aa 2 is Gly or Aib;

aa 16 is selected from the group consisting of Glu, Ser, Ala, Lys, and Aib;

aa 17 is selected from the group consisting of Gln, Lys, and U(X);

aa 20 is selected from the group consisting of Lys, Glu, and Arg;

aa 23 is lie or Val;

aa 24 is Ala or U(X);

aa 27 is Leu; and

aa 28 is Gln.

12. The peptide product of claim 1 having the structure:

(SEQ. ID. NO. 776)

His 1 -aa 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 -aa 16 -aa 17 -Arg 18 -Ala 19 -

aa 20 -Asp 21 -Phe 22 -aa 23 -aa 24 -Trp 25 -Leu 26 -aa 27 -aa 28 -

Thr 29 -NH 2 ;

wherein:

aa 2 is Gly or Aib;

aa 16 is selected from the group consisting of Glu, Ser, Ala, and Aib;

aa 17 is selected from the group consisting of Arg, hArg, and Gln,

aa 20 is Lys or U(X);

aa 23 is lie or Val;

aa 24 is selected from the group consisting of Gln, Ala, and U(X);

aa 27 is Leu; and

aa 28 is Gln.

13. The peptide product of claim 1 , wherein aa 16 and aa 20 are cyclized to form a lactam linkage.

14. The peptide product of claim 11 having the structure:

(SEQ. ID. NO. 778)

His 1 -aa 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 -aa 16 -aa 17 Ala 18 -Ala 19 -

aa 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega-X) 24 -Trp 25 -Leu 26 -

aa 27 -aa 28 -Thr 29 -NH 2 ;

wherein:

aa 2 is Aib or Gly;

aa 16 and aa 20 are each individually Lys or Glu and are cyclized through their side chains to form a lactam linkage;

aa 17 is selected from the group consisting of Arg, hArg, and Gln;

aa 27 is Leu;

aa 28 is Gln; and

X is a glucuronyl class moiety prepared from a 1-alkyl glycoside, and where the alkyl is a C 8 -C 20 linear alkyl chain.

15. The peptide product of claim 1 having the structure:

(SEQ. ID. NO. 780)

His 1 -aa 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 -aa 16 -aa 17 -Arg 18 -Ala 19 -

aa 20 -Asp 21 -Phe 22 -aa 23 -aa 24 -Trp 25 -Leu 26 -aa 27 -aa 28 -

Thr 29 -NH 2 ;

wherein:

aa 2 is Gly or Aib;

aa 16 is selected from the group consisting of Glu, Ala, and Aib;

aa 17 is Arg or hArg;

aa 20 is Lys(N-omega-X);

aa 23 is lie or Val;

aa 24 is Gln or Ala;

aa 27 is Leu; and

aa 28 is Gln;

wherein alkyl is a C 8 -C 20 linear alkyl chain.

16. A pharmaceutical composition comprising a therapeutically effective amount of a peptide product of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

17. The peptide product of claim 1 having the structure:

(SEQ. ID. NO. 795)

His 1 -aa 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 -U(X) 17 -Ala 18 -

Ala 19 -Lys 20 -Glu 21 -Phe 22 -Ile 23 -Ala 24 -Trp 25 -Leu 26 -Leu 27 -

aa 28 -Thr 29 -NH 2 ;

wherein:

aa 2 is Gly or Aib; and

aa 28 is Gln.

18. The peptide product of claim 11 having the structure:

(SEQ. ID. NO. 796)

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 -aa 16 -Gln 17 Ala 18 -Ala 19 -

aa 20 -Glu 21 -Phe 22 -Ile 23 -Lys(N-omega-X) 24 -Trp 25 -Leu 26 -

Leu 27 -aa 28 -Thr 29 -NH 2 ;

wherein:

aa 16 and aa 20 are each individually Lys or Glu and are cyclized through their side chains to form a lactam linkage;

aa 28 is Gln; and

X comprises a glucuronyl class moiety prepared from a 1-alkyl glycoside, and where alkyl is a C 8 -C 20 linear alkyl chain.

19. The peptide product of claim 11 having the structure:

(SEQ. ID. NO. 797)

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-X) 24 -Trp 25 -Leu 26 -Leu 27 -Gln 28 -

Thr 29 -NH 2 ;

wherein:

Glu 16 and Lys 20 are cyclized through their side chains to form a lactam linkage;

and X comprises a glucuronyl class moiety prepared from a 1-alkyl glycoside, and where alkyl is a C 8 -C 20 linear alkyl chain.

20. The peptide product of claim 1 , which is selected from the group consisting of:

(SEQ. ID. NO. 600)