| 主权项 |
1. An insulin analog comprising the structure:
X—Y—Z; wherein Z is an insulin peptide comprising an A chain and a B chain wherein the A chain comprises the sequence GIVEQCCX1SICSLYQLENX2CX3 (SEQ ID NO: 3), or an analog thereof comprising a sequence that differs from SEQ ID NO: 3 by 1 to 3 amino acid modifications, selected from positions A5, A8, A9, A10, A14, A15, A17, A18 and the B chain comprises the sequence of X14-X4LCGX5X6LVEALX7LVCGERGFX8 (SEQ ID NO: 14), or an analog thereof comprising a sequence that differs from SEQ ID NO: 14 sequence by 1 to 3 amino acid modifications, selected from positions B5, B13, B14, B17, B20, B22, and B23, said B chain being linked to said A chain through intermolecular disulfide linkages and optionally through an amide bond linkage between the carboxy terminus of the B chain and the amino terminus of the A chain to form a single chain polypeptide; and X—Y is a dipeptide linked via an amide bond to the N-terminal amino group of the A chain or B chain or to an amino group on a side chain of an amino acid of said A chain or B chain wherein X14 is a bond, or a 1 to 4 amino acid sequence selected from the group consisting of a FVNQ (SEQ ID NO: 11), VNQ, NQ and Q; X1 is selected from the group consisting of threonine and histidine; X2 is an amino acid of the general structure wherein X is selected from the group consisting of OH, NH2, NHR10 and OCH3, wherein R10 is a dipeptide of the general structure X—Y; X3 is selected from the group consisting of asparagine, ornithine, glycine, alanine, threonine, and serine; X4 is selected from the group consisting of histidine and threonine; X5 is selected from the group consisting of alanine, glycine and serine; X6 is selected from the group consisting of histidine, aspartic acid, glutamic acid, homocysteic acid and cysteic acid; X7 is an amino acid of the general structure wherein X12 is selected from the group consisting of OH, NH2, NHR11 and OCH3, wherein R11 is a dipeptide of the general structure X—Y; X8 is histidine, asparagine or an amino acid of the general structure wherein X13 is selected from the group consisting of H, OH, NH2, NHR12 and OCH3, wherein R12 is a dipeptide of the general structure X—Y; wherein X—Y comprises a dipeptide structure: wherein
R1 and R2 are independently selected from the group consisting of H, C1-C18 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl;R3 is C1-C18 alkyl;R4 is selected from the group consisting of CH3, CH2(C1-C10 alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2, CH2(C0-C3 alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2, CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12 alkyl)(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a pyrrolidine ring;R8 is H;R5 is NHR6, or OH;R6 is H or C1-C4 alkyl; and,R7 is selected from the group consisting of H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NHR6, aryl, and heteroaryl, wherein chemical cleavage half-life (t1/2) of X—Y from Z is at least about 1 hour to about 1 week in PBS under physiological conditions. |
