Glucagon analogs with enhanced solubility and stability in buffers with physiological pH values

摘要

1. Glucagon peptide with glucagon agonist activity, comprising the amino acid sequence of SEQ ED NO: 77, where Xaa at position 3 is an amino acid comprising a side chain of structure I, II or III:! ! Structure I! ! Structure II !! Structure III! where R1 is C0-3 alkyl or C0-3 heteroalkyl; R2 is NHR4 or C1-3 alkyl; R3 is C1-3alkyl; R4 is H or C1-3alkyl; X is NH, O or S; and Y is NHR4, SR3 or OR3,! or its analogue, comprising (i) an intramolecular bridge that connects the side chains of the amino acid at position i and the amino acid at position i + 4, where i is 12, 16, 20, or 24, (ii) an α, α-disubstituted amino acid in one, two, three or all positions of 16, 20, 21 and 24, or (iii) both (i) and (ii). ! 2. The glucagon peptide according to claim 1, where X is NH, or Y is NHR4. ! 3. The glucagon peptide according to claim 1, where R1 is C0-2 alkyl or C1 heteroalkyl. ! 4. The glucagon peptide according to claim 1, where R2 is NHR4 or C1 alkyl. ! 5. The glucagon peptide according to claim 1, where R4 is H or C1 alkyl. ! 6. The glucagon peptide according to claim 1, where Xaa at position 3 is an amino acid comprising a side chain! following structure:! (i) Structure I and R1 is CH2-S, X is NH, and R2 is CH3 (C (Acm);! (ii) Structure I and R1 is CH2, X is NH, R2 is CH3 (Dab (Ac)) ,! (iii) Structure I and R1 are C0alkyl, X is NH, R2 is NHR4, and R4 is H (Dap (urea));! (iv) Structure II and R1 is CH2, Y is NHR4 and R4 is CH3 ( Q (Me);! (V) Structure III and R1 are CH2 and R4 structure III is H (M (O)); or! (Vi) Structure I and R1 is CH2-CH2, X is NH and R2 is CH3 ( Orn (Ac)).! 7. The analogue of claim 1, wherein the α, α-disubstituted amino acid is AIB. !