Peptide pharmaceuticals for insulin resistance

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 a bond, H, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, or a steroid nucleus containing moiety;

R 1b , R 1c and R 1d are independently at each occurrence a bond, H, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group;

W 1 is independently at each occurrence —CH 2 —, —CH 2 —O—, —(C═O)—, —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C═S)—NH—, or —CH 2 —S—;

W 2 is independently at each occurrence —O—, —CH 2 —or —S—;

R 2 is independently at each occurrence a bond, a bond to U, H, a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, —NH 2 , —SH, C 2 -C 4 -alkene, C 2 -C 4 -alkyne, —NH(C═O)—CH 2 —Br, —(CH 2 ) m -maleimide, or —N 3 ,

n is 1, 2 or 3; and

m is 1-10;

the peptide has a structure of 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 -aa3 0 -aa 31 -aa 32 -

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

wherein:

Z is —OH or —NH—R 3 , wherein R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;

aa 1 is His, N—Ac-His, pGlu-His, or N—R 3 -His;

aa 2 is Ser, Ala, Gly, Aib, Ac4c, or Ac5c;

aa 3 is Gln or Cit;

aa 4 is Gly or D-Ala;

aa 5 is Thr or Ser;

aa 6 is Phe, Trp, F2Phe, Me2Phe, or Nal2;

aa 7 is Thr or Ser;

aa 8 is Ser or Asp;

aa 9 is Asp or Glu;

aa 10 is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO;

aa 11 is Ser, Asn, or U;

aa 12 is Lys, Glu, Ser, Arg, or U;

aa 13 is absent or Tyr, Gln, Cit, or U;

aa 14 is absent or Leu, Met, Nle, or U;

aa 15 is absent or Asp, Glu, or U;

aa 16 is absent or Ser, Gly, Glu, Aib, Ac5c, Lys, Arg, or U;

aa 17 is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U;

aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U;

aa 19 is absent or Ala, Val, Aib, Ac4c, Ac5c, or U;

aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U;

aa 21 is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U;

aa 22 is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U;

aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, or U;

aa 24 is absent or Gln, Ala, Glu, Cit, or U;

aa 25 is absent or Trp, Nal2, or U;

aa 26 is absent or Leu or U;

aa 27 is absent or Met, Val, Nle, Lys, or U;

aa 28 is absent or Asn, Lys, or U;

aa 29 is absent or Thr, Gly, Aib, Ac4c, Ac5c, or U;

aa 30 is absent or Lys, Aib, Ac4c, Ac5c, or U;

aa 31 is absent or Arg, Aib, Ac4c, Ac5c, or U;

aa 32 is absent or Asn, Aib, Ac4c, Ac5c, or U;

aa 33 is absent or Arg, Aib, Ac4c, Ac5c, or U;

aa 34 is absent or Asn, Aib, Ac4c, Ac5c, or U;

aa 35 is absent or Asn, Aib, Ac4c, Ac5c, or U;

aa 36 is absent or Ala, Ile, Aib, Ac4c, Ac5C, or U;

aa 37 is absent or U; and

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 11 -aa 37 is the linker amino acid U covalently attached to the surfactant X.

2. The peptide product of claim 1 , wherein n is 1.

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

4. The peptide product of claim 1 , wherein the surfactant X is comprised of 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecylbeta 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, or 1-octyl beta-D-diglucuronic acid, or functionalized 1-ecosyl 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, tetradecyl maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, or 1-octyl beta-D-maltoside, or the corresponding alpha anomer.

5. The peptide product of claim 1 , wherein the linker amino acid U is Lys, Cys, Orn, or an unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X.

6. The peptide product of claim 1 having the structure of 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 Formula III-A 

wherein:

Z is —OH or —NH—R 3 , wherein R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;

aa 1 is His, N—Ac-His, pGlu-His, or N—R 3 -His;

aa 2 is Ser, Ala, Gly, Aib, Ac4c, or Ac5c;

aa 3 is Gln or Cit;

aa 4 is Gly or D-Ala;

aa 5 is Thr or Ser;

aa 6 is Phe, Trp, F2Phe, Me2Phe, or Nal2;

aa 7 is Thr or Ser;

aa 8 is Ser or Asp;

aa 9 is Asp or Glu;

aa 10 is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO;

aa 11 is Ser, Asn, or U(X);

aa 12 is Lys, Glu, Ser, Arg, or U(X);

aa 13 is absent or Tyr, Gln, Cit, or U(X);

aa 14 is absent or Leu, Met, Nle, or U(X);

aa 15 is absent or Asp, Glu, or U(X);

aa 16 is absent or Ser, Gly, Glu, Aib, Ac5c, Lys, Arg, or U(X);

aa 17 is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U(X);

aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X);

aa 19 is absent or Ala, Val, Aib, Ac4c, Ac5c, or U(X);

aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U(X);

aa 21 is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X);

aa 22 is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U(X);

aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, or U(X);

aa 24 is absent or Gln, Ala, Glu, Cit, or U(X);

aa 25 is absent or Trp, Nal2, or U(X);

aa 26 is absent or Leu or U(X);

aa 27 is absent or Met, Val, Nle, Lys, or U(X);

aa 28 is absent or Asn, Lys, or U(X); and

aa 29 is absent or Thr, Gly, Aib, Ac4c, Ac5c, or 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 16 -aa 29 is the natural or unnatural amino acid U covalently attached to the surfactant X.

7. The peptide product of claim 1 , wherein aa 18 is a lysine residue attached to the surfactant X.

8. The peptide product of claim 1 , wherein aa 2 is an Aib or Ac4c residue.

9. The peptide product of claim 1 , wherein the peptide comprises one or more Aib residues.

10. The peptide product of claim 1 , wherein aa 12 and aa 16 , or aa 16 and aa 20 , are cyclized through their side chains to form a lactam linkage.

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

(SEQ. ID. NO. 321)

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-1′-alkyl beta-D-glucuronyl) 24 -Trp 25 -

Leu 26 -aa 27 -Asn 28 -Thr 29 -NH 2 ; 

wherein:

aa 2 is Aib or Ac4c;

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

aa 17 is Arg, hArg or Gln;

aa 27 is Met or Nle; and

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

12. The peptide product of claim 1 , wherein the surfactant X comprises an octyl, decyl, dodecyl, tetradecyl or hexadecyl alkyl group.

13. 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.

14. A method of treating a condition associated with insulin resistance, comprising administration of a therapeutically effective amount of a peptide product of claim 1 to an individual in need thereof.

15. A method of treating a cardiovascular disease, comprising administration of a therapeutically effective amount of a peptide product of claim 1 to an individual in need thereof.

16. A method of treating diabetes, comprising administration of a therapeutically effective amount of a peptide product of claim 1 to an individual in need thereof.

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

wherein:

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.

18. The peptide product of claim 1 , wherein at least one occurrence of R 1a is a substituted or unsubstituted C 6 -C 20 alkyl group.

19. The peptide product of claim 1 having the structure of 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 -Z Formula III-B 

wherein:

Z is —OH or —NH—R 3 , wherein R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl, or a PEG chain of less than 10 Da;

aa 2 is Ser, Ala, Gly, Aib, Ac4c, or Ac5c;

aa 3 is Gln or Cit;

aa 6 is Phe, Trp, F2Phe, Me2Phe, or Nal2;

aa 10 is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO;

aa 11 is Ser, Asn, or U(X);

aa 12 is Lys, Glu, Ser, or U(X);

aa 13 is absent or Tyr, Gln, Cit, or U(X);

aa 14 is absent or Leu, Met, Nle, or U(X);

aa 15 is absent or Asp, Glu, or U(X);

aa 16 is absent or Ser, Gly, Glu, Aib, Ac5c, Lys, or U(X);

aa 17 is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U(X);

aa 18 is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X);

aa 19 is absent or Ala, Val, Aib, Ac4c, Ac5c, or U(X);

aa 20 is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U(X);

aa 21 is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X);

aa 22 is absent or Phe, Aib, Ac4c, Ac5c, or U(X); and

aa 23 is absent or Val, Ile, Aib, Ac4c, Ac5c, or 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 16 -aa 23 is the natural or unnatural amino acid U covalently attached to the surfactant X.

20. A peptide product selected from the group consisting of EU-A300 through EU-A599.