Peptide pharmaceuticals for insulin resistance

1. A peptide selected from 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 OH, N-R 4 —His, or —NH-R 3 ,

wherein

R 3 is H, substituted or unsubstituted C 1 -C 12 alkyl;

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 Aib;

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, or Bip 2 EtMeO;

aa 11 is Ser, Asn, or Bip;

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

aa 13 is Tyr, Gln, or Cit;

aa 14 is Leu, Met, or Nle;

aa 15 is Asp, or Glu;

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

aa 17 is Lys;

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

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

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

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

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

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

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

aa 25 is Trp, or Nal2;

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

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

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

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

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

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

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

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

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

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

aa 37 is absent;

wherein any two of aa 1 -aa 36 are optionally cyclized through their side chains to form a lactam linkage.

2. The peptide 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;

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

aa 2 is Aib;

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, or Bip2EtMeO;

aa 11 is Ser, Asn, or Bip;

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

aa 13 is Tyr, Gln, or Cit;

aa 14 is Leu, Met, or Nle;

aa 15 is Asp, or Glu;

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

aa 17 is Lys;

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

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

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

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

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

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

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

aa 25 is Trp, or Nal2;

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln; and

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

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

3. The peptide 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 l9 -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;

aa 2 is Aib;

aa 3 is Gln or Cit;

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

aa 10 is Tyr, Nal2, Bip, or Bip 2 EtMeO;

aa 11 is Ser, Asn, or Bip;

aa 12 is Lys, Glu, or Ser;

aa 13 is Tyr, Gln, or Cit;

aa 14 is Leu, or Nle;

aa 15 is Asp, or Glu;

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

aa 17 is Lys;

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

aa 19 is Ala, or Aib;

aa 20 is Gln, Lys, Arg, Cit, Glu, or Aib;

aa 21 is Asp, Glu, Leu, or Aib;

aa 22 is Phe;

aa 23 is Val, Ile, or Aib;

aa 24 is Ala, or Gln;

aa 25 is Trp;

aa 26 is Leu;

aa 27 is Leu;

aa 28 is Gln;

aa 29 is Thr, or Aib; and

aa 30 is absent or is Arg;

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

4. The peptide of claim 2 , having the structure of Formula III-A

Formula III-A

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 H, or C 1 -C 12 substituted or unsubstituted alkyl;

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, or Lys;

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 Lys;

aa 18 is Ala;

aa 19 is Ala;

aa 20 is Lys, or Glu;

aa 21 is Glu;

aa 22 Phe;

aa 23 is Ile;

aa 24 is Gln, or Glu;

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.

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

6. The peptide of claim 1 , further comprising a covalently linked glycoside surfactant and/or one or more PEG moieties.

7. The peptide of claim 6 , wherein the glycoside surfactant is an alkyl glycoside.

8. The peptide of claim 6 , wherein the one or more PEG moieties is a PEG chain comprising C 10 -C 300 .

9. The peptide of claim 1 , further comprising a hydrophilic group and a hydrophobic group covalently linked, wherein the hydrophilic group is selected from a glycoside or one or more PEG moieties and the hydrophobic group is selected from a C 1 -C 30 alkyl group, a substituted or unsubstituted 1-alkoxyaryl group, or a substituted or unsubstituted 1-aralkyl group.

10. The peptide of claim 9 , wherein the hydrophilic group is a glycoside.

11. The peptide of claim 9 , wherein the hydrophilic group is one or more PEG moieties.

12. The peptide of claim 9 , wherein the hydrophobic group is a C 1 -C 30 alkyl group.

13. The peptide of claim 1 , further comprising a covalently linked C 1 -C 30 alkyl group, a substituted or unsubstituted 1-alkoxyaryl group, or a substituted or unsubstituted 1-aralkyl group.

14. The peptide of claim 6 , wherein the glycoside surfactant and/or one or more PEG moieties is covalently linked to a lysine of aa17 or aa20.

15. The peptide of claim 6 , wherein the covalent modification of the peptide prolongs duration of action of the peptide.

16. A method of treating or treating effects of insulin resistance comprising administration of a peptide of claim 1 to an individual in need thereof.

17. A method of treating or treating effects of insulin resistance comprising administration of a glucagon peptide analog comprising amino acid residues aa 1 -aa 27 of SEQ. ID. NO. 1 according to claim 1 to the individual in need thereof.

18. The method of claim 17 , wherein the administration of said glucagon analog causes weight loss.