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 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, or a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, a protecting group, a saccharide, 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 —O—, —CH 2 — or —S—;

R 2 is independently, at each occurrence, a bond to U, H, a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group, —NH—, —S—, -triazolo-, —NH(C═O)—CH 2 —, —(CH 2 ) m -maleimide-;

n is 1, 2 or 3; and

m is an integer of 1-10;

the peptide is selected from 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

Formula II

wherein:

Z is OH, N—R 4 -His, 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;

R 4 is a C 2 -C 10 acyl group, for example Ac or Bz;

aa 1 is His, N—R 4 -His, pGlu-His, or N—R 3 -His;

aa 2 is Ser, D-Ser, Ala, Gly, Pro, MePro, 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, 2FPhe, MePhe, 2FMePhe, 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, Bip2EtMeO, or U;

aa 11 is absent or Ser, Asn, Bip, or U;

aa 12 is absent or 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, Ala, Aib, Ac5c, Lys, Arg, or U;

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

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

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is Thr;

aa 30 is absent or Lys, Aib, Ac4c, Ac5c, Arg, 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 Ile, Aib, Ac4c, Ac5C, or U;

aa 36 is absent or Ala, Aib, Ac4c, Ac5C, or 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 25 or aa 30 -aa 37 is the linker amino acid U covalently attached to X.

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

3 . A peptide product of claim 1 , wherein X has the structure:

wherein:

R 1a is H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, or a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, a saccharide, or a substituted or unsubstituted C 1 -C 30 alkyl 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 —O—, —S—;

R 2 is a bond, —NH—, —S—, —NH(C═O)—CH 2 — or —(CH 2 ) m -maleimide-; and

m is an integer of 1-10.

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

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

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

wherein:

R 1a is H, a protecting group, a saccharide, a substituted or unsubstituted C 1 -C 30 alkyl group, or a steroid nucleus containing moiety;

R 1b , R 1c , and R 1d are each, independently at each occurrence, H, a protecting group, or a substituted or unsubstituted C1-C30 alkyl group;

W 1 is —(C═O)—NH—;

W 2 is —O—; and

R 2 is a bond.

7 . The peptide product of claim 3 , wherein 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.

8 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 1 -C 30 alkyl group.

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

10 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 12 -C 20 alkyl group.

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

12 . The peptide product of claim 1 , wherein X comprises 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, or 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 or 6,6′-dicarboxylates.

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

14 . 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, MePro, 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, 2FPhe, MePhe, 2FMePhe, 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, Bip2EtMeO, or U(X);

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

aa 12 is absent or 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, Ala, Aib, Ac5c, Lys, Arg, or U(X);

aa 17 is absent or Arg, hArg, Gln, Glu, Lys, 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 2l 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 Ala, Gln, Glu, Cit, or U(X);

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

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is Thr;

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 , or aa 25 , is the natural or unnatural amino acid U covalently attached to X.

15 . 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 -aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -

aa 29 -aa 30 -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 Gly, MePro or Aib;

aa 3 is Gln or Cit;

aa 6 is Phe, 2FPhe, MePhe, 2FMePhe, or Nal2;

aa 10 is Tyr, Nal2, Bip, Bip2EtMeO, or U(X);

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

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

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

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

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

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

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

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

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

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

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

aa 22 is absent or Phe, or U(X)

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

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

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

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is Thr;

aa 30 is absent or Arg 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 10 , aa 11 , aa 12 , aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , or aa 24 , is the natural or unnatural amino acid U covalently attached to X.

16 . The peptide product of claim 1 , wherein aa 17 is a lysine residue attached to X.

17 - 33 . (canceled)

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

35 . A method of treating a condition associated with insulin resistance comprising administration of a peptide product of claim 1 to an individual in need thereof.

36 - 40 . (canceled)

41 . The method of claim 35 , wherein the administration of said glucagon analog causes weight loss.

42 - 78 . (canceled)

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

(SEQ. ID. NO. 1110)

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, or C 1 -C 12 substituted or unsubstituted alkyl, or a PEG chain of less than 10 Da;

aa 1 is His;

aa 2 is Aib;

aa 3 is Gln;

aa 4 is Gly;

aa 5 is Thr;

aa 6 is Phe;

aa 7 is Thr;

aa 8 is Ser;

aa 9 is Asp;

aa 10 is Tyr, Glu, Lys, or U(X);

aa 11 is Ser;

aa 12 is Lys or Glu;

aa 13 is Tyr;

aa 14 is Leu, Glu, or Lys;

aa 15 is Asp;

aa 16 is Glu or Lys;

aa 17 is Gln, Glu, or U(X);

aa 18 is Ala;

aa 19 is Ala;

aa 20 is Lys, Glu or U(X);

aa 21 is Glu;

aa 22 Phe;

aa 23 is Ile;

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

aa 25 is Trp;

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is Thr;

wherein aa 16 and aa 20 , or aa 10 and aa 14 , or aa 12 and aa 16 are optionally cyclized through their side chains to form a lactam linkage; and

provided that one, or at least one of aa 10 , aa 17 , aa 20 , or aa 24 is the natural or unnatural amino acid U covalently attached to X.