IMPROVED 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 amino acid residues aa 1 -aa 20 of SEQ. ID. NO. 1:

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 each, 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 —O—, —CH 2 — or —S—;

R 2 is a bond to U,

n is 1, 2 or 3; and

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 OH, or —NH—R 3 , wherein R 3 is H, or C1-C 12 substituted or unsubstituted 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 Tyr, Gln, Cit, or U;

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

aa 15 is Asp, Glu, or U;

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

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

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

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

aa 20 is 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 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 11 -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 X.

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

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

wherein:

R 1a is H, a protecting group, 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 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—; and,

R 2 is a bond to U.

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

5 . (canceled)

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

wherein:

R 1a is H, a protecting group, 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 C 1 -C 30 alkyl group;

W 1 is —(C═O);

W 2 is —O—;

R 2 is a bond to U.

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);

W 2 is —O—; and

R 2 is a bond to U.

8 . The peptide product of claim 1 , wherein R 1a is a substituted or unsubstituted C 1 -C 30 alkyl group, a substituted or unsubstituted C 6 -C 20 alkyl group, or a substituted or unsubstituted C 12 -C 2 alkyl group.

9 . (canceled)

10 . (canceled)

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 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, 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, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, or 1-octyl beta-D-maltoside.

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

14 - 18 . (canceled)

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

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

21 - 24 . (canceled)

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

26 - 31 . (canceled)

32 . 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.

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

34 . The method of claim 33 , wherein the insulin resistance is diabetes or cardiovascular disease.

35 - 38 . (canceled)

39 . The method of claim 33 , wherein the administration of said peptide product causes weight loss.

40 - 57 . (canceled)

58 . The peptide product of claim 1 , wherein the peptide comprises at least aa 1 -aa 26 of SEQ ID NO. 1.

59 . The peptide product of claim 58 , wherein aa 17 is U(X) and aa 16 and aa 20 are cyclized to form a lactam linkage.

60 . The peptide product of claim 59 , 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);

W 2 is —O—; and

R 2 is a bond to U.