Stable analogs of peptide and polypeptide therapeutics
The present invention relates to compositions of peptide and polypeptide analogs that are resistant to proteolysis, pharmaceutical uses thereof, and methods of preparation thereof.
1. A DPP IV-resistant analog of a biologically active peptide or polypeptide factor, wherein
the peptide or polypeptide factor is capable of binding a GLP-1-receptor;
the analog of the peptide or polypeptide factor is capable of binding a GLP-1 receptor;
the analog of the peptide or polypeptide factor is represented by Xaa-Ala-Yaa-R or Xaa-Pro-Yaa-R;
Xaa is an N-terminal amino acid residue;
R is
GTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 19),
GTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
(SEQ ID NO: 20),
GTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 (SEQ ID NO: 21),
GSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO: 22),
GTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ
(SEQ ID NO: 23),
KPDNPGEDAPAEDMARYYSALRHYINLITRQRY
(SEQ ID NO: 24),
EPVYPGDNATPEQMAQYAADLRRY (SEQ ID NO: 25) or
KPEAPGEDASPEELNRYYASLRHYLNLVTRQRY
(SEQ ID NO: 26);
Yaa is an amino acid residue represented by Formula I:
R 1 and R 2 are, independently for each occurrence, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, halogen, hydroxyl, amine, or cyano; or R 1 and R 2 taken together form a ring of 4-7 atoms;
R 3 is lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkoxyl, halogen, carboxyl, carboxamide, carbonyl, cyano, thioalkyl, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate,
sulfonamido, —(CH 2 ) m R 4 , —(CH 2 ) m OH, —(CH 2 ) m COOH, —(CH 2 ) m O-lower alkyl, —(CH 2 ) m O-lower alkenyl, —(CH 2 ) n O(CH 2 ) m R 4 , —(CH 2 ) m SH, —(CH 2 ) m S-lower alkyl, —(CH 2 ) m S-lower alkenyl, —(CH 2 ) n S(CH 2 ) m R 4 , —(CH 2 ) m NH 2 , —(CH 2 ) m NC(═NH)NH 2 , —(CH 2 ) m C(═O)NH 2 , or —(CH 2 ) m NH 2 ;
R 4 is, independently for each occurrence, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl;
m is 0, 1, or 2; and
n is 0, 1, or 2.
2. The DPP IV-resistant analog of claim 1 , wherein the analog of the peptide or polypeptide factor is represented by Xaa-Ala-Yaa-R.
3. The DPP IV-resistant analog of claim 1 , wherein the analog of the peptide or polypeptide factor is represented by Xaa-Pro-Yaa-R.
4. The DPP IV-resistant analog of claim 1 , wherein n is 0.
5. The DPP IV-resistant analog of claim 1 , wherein R is
(SEQ ID NO: 19)
GTFTSDVSSYLEGQAAKEFIAWLVKGR,
(SEQ ID NO: 20)
GTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2,
(SEQ ID NO: 21)
GTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2,
(SEQ ID NO: 22)
GSFSDEMNTILDNLAARDFINWLIQTKITD,
or
(SEQ ID NO: 23)
GTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ.
6. The DPP IV-resistant analog of claim 1 , wherein R is
(SEQ ID NO: 24)
KPDNPGEDAPAEDMARYYSALRHYINLITRQRY,
(SEQ ID NO: 25)
EPVYPGDNATPEQMAQYAADLRRY,
or
(SEQ ID NO: 26)
KPEAPGEDASPEELNRYYASLRHYLNLVTRQRY.
7. The DPP IV-resistant analog of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of methyl, ethyl, and propyl.
8. The DPP IV-resistant analog of claim 1 , wherein R 1 and R 2 are both methyl.
9. The DPP IV-resistant analog of claim 1 , wherein R 3 is selected from the group consisting of lower alkyl, phenyl, hydroxyphenyl, indole, imidazole,
hydroxyl, —COOH, —CH 2 COOH, —CH 2 CH 2 NC(═NH)NH 2 , —CH 2 C(═O)NH 2 , —CH 2 CH 2 C(═O)NH 2 , —SH, and —CH 2 SCH 3 .
10. The DPP IV-resistant analog of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of methyl, ethyl, and propyl; and R 3 is selected from the group consisting of lower alkyl, phenyl, hydroxyphenyl, indole, imidazole,
hydroxyl, —COOH, —CH 2 COOH, —CH 2 CH 2 NC(═NH)NH 2 , —CH 2 C(═O)NH 2 , —CH 2 CH 2 C(═O)NH 2 , —SH, and —CH 2 SCH 3 .
11. The DPP IV-resistant analog of claim 1 , wherein R 1 and R 2 are both methyl; and R 3 is selected from the group consisting of lower alkyl, phenyl, hydroxyphenyl, indole, imidazole,
hydroxyl, —COOH, —CH 2 COOH, —CH 2 CH 2 NC(═NH)NH 2 , —CH 2 C(═O)NH 2 , —CH 2 CH 2 C(═O)NH 2 , —SH, and —CH 2 SCH 3 .
12. The DPP IV-resistant analog of claim 1 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.
13. The DPP IV-resistant analog of claim 2 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.
14. The DPP IV-resistant analog of claim 3 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.
15. The DPP IV-resistant analog of claim 4 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.
16. The DPP IV-resistant analog of claim 5 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.
17. The DPP IV-resistant analog of claim 6 , wherein R 1 and R 2 are both methyl; and R 3 is —COOH or —CH 2 COOH.