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 proteinase-resistant analog of GLP-1 with an amino acid sequence represented by:
Xaa-Ala-Yaa-R
wherein
Xaa is His;
R is a polypeptide having an amino acid sequence selected from the group consisting of
GTFTSDVSSYLEGQAAKEFIAWLVKGRG,
GTFTSDVSSYLEGQAAKEFIAWLVKGR—NH 2 ,
GTFTSDVSSYLEGQAAKEFIAWLVKGR,
GTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS—NH 2 ,
GTFTSDLSKEMEEEAVRLFIEWLKNGGPSSGAPPPS, and
GTFTSDLSKEMEEEAVRLFIEWLKNGGPSSGAPPPS—NH 2 ; and
Yaa is an amino acid analog of Formula II:
wherein
R 1 and R 2 are independently for each occurrence lower alkyl or halogen;
R 3 is selected from the group consisting of lower alkyl, aryl, —OH, —(CH 2 ) m —COOH, —(CH 2 ) m —NH 2 , —(CH 2 ) m —N—C(═NH)NH 2 , —(CH 2 ) m —C(═O)NH 2 , —SH, and —(CH 2 ) m —S—CH 3 ; and
m is 0, 1, or 2.
2. The proteinase-resistant analog of claim 1 , wherein Yaa is an amino acid analog represented by:
3. The proteinase-resistant analog of claim 1 , wherein Yaa is an amino acid analog represented by:
4. A proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2
(SEQ ID NO:11)
wherein X is an amino acid analog of Formula II:
wherein
R 1 and R 2 are independently selected from a lower alkyl or a halogen;
R 3 is selected from lower alkyl, aryl, hydroxyl group, —(CH 2 ) m —COOH, —(CH 2 ) m —NH 2 , —(CH 2 ) m —N—C(═NH)NH 2 , —(CH 2 ) m —C(═O)NH 2 , —SH, and —(CH 2 ) m —S—CH 3 ; and
m is 0, 1, or 2.
5. A proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRG
(SEQ ID NO: 10)
wherein X is an amino acid analog of Formula II:
wherein
R 1 and R 2 are independently selected from a lower alkyl or a halogen;
R 3 is selected from lower alkyl, aryl, hydroxyl group, —(CH 2 ) m —COOH, —(CH 2 ) m —NH 2 , —(CH 2 ) m —N—C(═NH)NH 2 , —(CH 2 ) m —C(═O)NH 2 , —SH, and —(CH 2 ) m —S—CH 3 ; and
m is 0, 1, or 2.
6. A proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:
(SEQ ID NO: 36)
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH 2
wherein X is an amino acid analog of Formula II:
wherein
R 1 and R 2 are independently selected from a lower alkyl or a halogen;
R 3 is selected from lower alkyl, aryl, hydroxyl group, —(CH 2 ) m —COOH, —(CH 2 ) m —NH 2 , —(CH 2 ) m —N—C(═NH)NH 2 , —(CH 2 ) m —C(═O)NH 2 , —SH, and —(CH 2 ) m —S—CH 3 ; and
m is 0, 1, or 2.