Peptide pharmaceuticals

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

wherein X is

wherein:

A is a hydrophobic group which is a substituted or unsubstituted C 8 -C 20 alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, or a steroid nucleus-containing moiety, and which is attached to a saccharide at the C-1 position of the saccharide via an O- or S-glycosidic bond; and

B is a hydrophilic saccharide group covalently attached to the peptide via the carboxy terminus of the peptide or a side chain of the linker amino acid U.

2. The peptide product of claim 1 , wherein the saccharide is selected from glucose, galactose, mannose, melibiose, maltose, glucuronic acid, galacturonic acid, diglucuronic acid, mannouronic acid, melibiouronic acid and maltouronic acid.

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

4. The peptide product of claim 1 , wherein the hydrophilic group of the surfactant is attached to the peptide via an amide bond.

5. The peptide product of claim 1 , wherein the surfactant 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, 1-eicosyl beta-D-melibiouronic acid, 1-octadecyl beta-D-melibiouronic acid, 1-hexadecyl beta-D-melibiouronic acid, 1-tetradecyl beta-D-melibiouronic acid, 1-dodecyl beta-D-melibiouronic acid, 1-decyl beta-D-melibiouronic acid, 1-octyl beta-D-melibiouronic 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, 1-octyl beta-D-maltoside, 1-eicosyl beta-D-melibiose, 1-octadecyl beta-D-melibiose, 1-hexadecyl beta-D-melibiose, 1-tetradecyl beta-D-melibiose, 1-dodecyl beta-D-melibiose, 1-decyl beta-D-melibiose, or 1-octyl beta-D-melibiose.

6. The peptide product of claim 1 , wherein the peptide is an opioid peptide.

7. The peptide product of claim 6 , wherein the peptide product has a structure of Formula IA:

aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Z Formula IA

wherein:

each of aa 1 , aa 2 , aa 3 , aa 4 , and aa 5 is independently absent, a D- or L-natural or unnatural amino acid, an N-alkylated amino acid, an N-acetylated amino acid, a CαR 3 amino acid, a Ψ-amino acid, or a linker amino acid U covalently attached to the surfactant X;

Z is OH, NH 2 or —NHR 3 ;

each R 3 is independently substituted or unsubstituted C 1 -C 12 branched or straight chain alkyl, a PEG chain of less than 10 Da, or a substituted or unsubstituted aralkyl chain;

provided that one, or at least one, of aa 1 , aa 2 , aa 3 , aa 4 , and aa 5 is the linker amino acid U covalently attached to the surfactant X; and

further provided that not all of aa 1 , aa 2 , aa 3 , aa 4 , and aa 5 are absent.

8. A peptide product having a structure of Formula II:

aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Z Formula II

wherein:

each of aa 1 , aa 2 , aa 3 , aa 4 , and aa 5 is independently a D- or L-natural or unnatural amino acid, an N-alkylated amino acid, an N-acetylated amino acid, a CαR 3 amino acid, a Ψ-amino acid, or a linker amino acid U covalently attached to a surfactant X, or aa 5 can be absent;

Z is —OH, —NH 2 or —NHR 3 ;

each R 3 is independently substituted or unsubstituted C 1 -C 12 branched or straight chain alkyl, a PEG chain of less than 10 Da, or a substituted or unsubstituted aralkyl chain; and

X is

wherein:

A is a hydrophobic group which is 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, and which is attached to a saccharide at the C-1 position of the saccharide via an O- or S-glycosidic bond; and

B is a hydrophilic saccharide group covalently attached to the peptide via the carboxy terminus of the peptide or a side chain of a linker amino acid U;

provided that one, or at least one, of aa1, aa2, aa3, aa4, and aa5 is a linker amino acid U covalently attached to the surfactant X; and

further provided that at least aa 1 , aa 2 , aa 3 , and am are present.

9. The peptide product of claim 8 , wherein the peptide product has a structure of Formula III:

(SEQ. ID. NO. 1)

aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Z Formula III

wherein:

aa 1 is Tyr, Dmt, N—R 3 -Tyr, N—R 3 -Dmt, N—(R 3 ) 2 -Tyr, or N—(R 3 ) 2 -Dmt;

aa 2 is Pro, D-Arg, D-U(X), D-Ala, D-Cit, Tic, or Tic(Ψ[CH2-NH]);

aa 3 is Phe, Trp, Tmp, D- or L-Nal(1), D- or L-Nal(2), CαMePhe, or Ψ-Phe;

aa 4 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), U(X), or D- or L-CαMeU(X);

aa 5 is absent or Pro, Aib, U(X), or D- or L-CαMeU(X); and

U is a linker amino acid covalently attached to the surfactant X and is a dibasic or diacidic natural or unnatural amino acid, a natural or unnatural amino acid comprising a thiol, an unnatural amino acid comprising a —N 3 group, an unnatural amino acid comprising an acetylenic group, or an unnatural amino acid comprising a —NH—C(═O)—CH 2 —Br or a —(CH 2 ) m -maleimide group, wherein m is 1-10.

10. The peptide product of claim 9 , wherein X has the structure:

wherein:

A is a substituted or unsubstituted C 1 -C 30 alkyl chain, 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, 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— or —S—;

R 2 is a bond, C 2 -C 4 -alkene, C 2 -C 4 -alkyne, or —(CH 2 ) m -maleimide;

m is 1-10; and

n is 1, 2 or 3.

11. The peptide product of claim 10 , wherein X has the structure:

12. The peptide product of claim 10 , wherein X has the structure:

wherein:

(1) A is 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)—NH—;

W 2 is —O—; and

R 2 is a bond, or

(2) A 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.

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

14. The peptide product of claim 9 , (SEQ. ID. NO. 149)

wherein:

U is a dibasic natural or unnatural amino acid;

X is a surfactant of the 1-alkyl glycoside class wherein 1-alkyl is substituted or unsubstituted C 1 -C 20 alkyl or a substituted or unsubstituted aralkyl group;

Z is NH 2 ;

aa 1 is Tyr, Dmt, Nα-Me-Tyr, Nα-Me-Dmt, N,Nα-diMe-Tyr, or N,Nα-diMe-Dmt;

aa 2 is Pro, D-Arg, D-U(X), D-Ala, D-Cit, Tic, or Tic(Ψ[CH2-NH]);

aa 3 is Phe, Trp, Tmp, D- or L-Nal(1), D- or L-Nal(2), CaMePhe, or W-Phe;

aa 4 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), U(X), or D- or L-CαMeU(X); and

aa 5 is absent or Pro, Aib, U(X), or D- or L-CαMeU(X).

15. The peptide product of claim 14 , (SEQ. ID. NO. 150)

wherein:

X is comprised of 1-alkyl glucuronic acid or 1-alkyl diglucuronic acid;

Z is NH 2 ;

aa 1 is Dmt;

aa 2 is Pro, D-Lys(X), Tic, or Tic(Ψ[CH2-NH]);

aa 3 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), or W-Phe;

aa 4 is Phe, D- or L-Nal(1), D- or L-Nal(2), or Lys(X); and

aa 5 is absent or Pro, Aib, Lys(X), or D- or L-CαMeLys(X).

16. The peptide product of claim 15 ,

wherein:

(1) aa 1 is Dmt; (SEQ. ID. NO. 151)

aa 2 is Pro;

aa 3 is Phe or Tmp;

aa 4 is Phe or Lys(X); and

aa 5 is absent or Aib, Lys(X), or D- or L-CαMeLys(X); or

(2) aa 1 is Dmt; (SEQ. ID. NO. 152)

aa 2 is Pro;

aa 3 is Phe or Tmp;

aa 4 is Phe or Lys(X); and

aa 5 is absent or Lys(X).

17. The peptide product of claim 9 , (SEQ. ID. NO. 153) wherein:

U is a dibasic natural or unnatural amino acid;

X is a surfactant of the 1-alkyl glycoside class wherein the 1-alkyl group of the 1-alkyl glycoside is substituted or unsubstituted C 1-20 alkyl or a substituted or unsubstituted aralkyl group;

aa 1 is Tyr, Dmt, N—R 3 -Tyr, N—R 3 -Dmt, N—(R 3 ) 2 -Tyr, or N—(R 3 ) 2 -Dmt;

aa 2 is D-Arg, D-Cit or D-U(X);

aa 3 is Phe, Trp, D- or L-Nal(1), D- or L-Nal(2), or Tmp;

aa 4 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), U(X), or D- or L-CαMeU(X); and

aa 5 is absent or Pro or U(X).

18. The peptide product of claim 17 , (SEQ. ID. NO. 154)

wherein:

X is a surfactant of the 1-alkyl glucuronic acid or 1-alkyl diglucuronic acid class;

aa 1 is Dmt, Nα-Me-Dmt, or N,Nα-diMe-Dmt;

aa 2 is D-Arg, D-Cit, D-Lys(X), or D-Orn(X);

aa 3 is Phe or Tmp;

aa 4 is Phe, Tmp, Lys(X), or Orn(X); and

aa 5 is absent or Pro, Lys(X), or Orn(X).

19. The peptide product of claim 9 ,

wherein:

(1) U is a dibasic natural or unnatural amino acid; (SEQ. ID. NO. 155)

X is a surfactant of the 1-alkyl glycoside class wherein 1-alkyl is substituted or unsubstituted C 1 -C 20 alkyl or a substituted or unsubstituted aralkyl group;

Z is NH 2 ;

aa 1 is Tyr, Dmt, N—R 3 -Tyr, N—R 3 -Dmt, N—(R 3 ) 2 -Tyr, or N—(R 3 ) 2 -Dmt;

aa 2 is Tic or Tic(Ψ[CH2-NH]);

aa 3 is Phe, Tmp, or Ψ-Phe when aa 2 is Tic(Ψ[CH2-NH]);

aa 4 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), or U(X); and

aa 5 is absent or Pro, Aib, or U(X); or

(2) X is a surfactant of the 1-alkyl glucuronic acid or 1-alkyl diglucuronic acid class; (SEQ. ID. NO. 156)

aa 1 is Tyr, Dmt, Nα-Me-Tyr, Nα-Me-Dmt, N,Nα-diMe-Tyr, or N,Nα-diMe-Dmt;

aa 2 is Tic or Tic(Ψ[CH2-NH]);

aa 3 is Phe, Tmp, or Ψ-Phe when aa 2 is Tic(Ψ[CH2-NH]);

aa 4 is Phe, Tmp, D- or L-Nal(1), D- or L-Nal(2), Lys(X), or Orn(X); and

aa 5 is absent or Aib, Lys(X), or Orn(X); or

(3) X comprises 1-alkyl glucuronic acid or 1-alkyl diglucuronic acid; (SEQ. ID. NO. 157)

aa 2 is Tic or Tic(Ψ[CH2-NH]);

aa 3 is Phe or Ψ-Phe;

aa 4 is Lys(X); and

aa 5 is absent.

20. The peptide product of claim 19 , (SEQ. ID. NO. 158)

wherein:

X is comprised of 1-alkyl glucuronic acid;

aa 2 is Tic;

aa 3 is Phe;

aa 4 is Lys(X); and

aa 5 is absent.

21. The peptide product of claim 20 , which is selected from:

(SEQ. ID. NO. 78)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-methyl beta-D-

glucuronyl)-NH 2 ;

(SEQ. ID. NO. 80)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-octyl beta-D-

glucuronyl)-NH 2 ;

(SEQ. ID. NO. 81)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-decyl beta-D-

glucyronyl)-NH 2 ;

(SEQ. ID. NO. 79)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-dodecyl beta-D-

glucuronyl)-NH 2 ;

(SEQ. ID. NO. 160)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-tetradecyl beta-D-

glucuronyl)-NH 2 ;

(SEQ. ID. NO. 82)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-hexadecyl beta-D-

glucuronyl)-NH 2 ;

(SEQ. ID. NO. 83)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-octadecyl beta-D-

glucuronyl)-NH 2 ; and

(SEQ. ID. NO. 84)

H-Dmt-Tic-Phe-Lys(N-epsilon-1-eicosyl beta-D-

glucuronyl)-NH 2 .

22. 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.

23. The peptide product of claim 8 , which is used in the treatment of pain.

24. The peptide product of claim 1 , which displays improved duration of action, bioavailability, stability, receptor binding potency or cellular activation potency in comparison to the unmodified peptide not covalently attached to the surfactant X.