NOVELTY - A peptide conjugate (I) comprising a peptide (X) which is an exendin at least 90 % homologous to exendin-4, a variant of exendin comprising 1-5 deletions at positions 34-39 or a Lys at position 40 having a lipophilic substituent (LS), a glucagon-like peptide (GLP-1) (7-36) or GLP-1 (7-37) substituted by D-Ala, Gly or alpha-amino isobutyric acid for Ala at position 8 or LS, or a sequence (Z), is new.
USE - PC and (I) are useful in therapy. (I), (Ia) and (II) are useful in the manufacture of a pharmaceutical composition for use in treatment of type 1 or type 2 diabetes, insulin resistance syndrome, obesity, eating disorder, hyperglycemia, metabolic disorders and gastric disease. (Ia), (I) and (II) are useful in the manufacture of a pharmaceutical composition for use in the treatment of disease states associated with elevated blood glucose levels elicited by hormones known to increase blood glucose levels, such as catechol amines including adrenalin, glucocorticoids, growth hormone and glucagon. (Ia), (I) and (II) are useful in the manufacture of a pharmaceutical composition for use, in mammal, in regulation of blood glucose levels, preferably lowering blood glucose levels, in regulation of gastric emptying, for stimulating insulin release, for lowering plasma lipid level, and for reducing mortality and morbidity after myocardial infarction. (All claimed).
DETAILED DESCRIPTION - A peptide conjugate (I) comprising a peptide (X) which is an exendin at least 90 % homologous to exendin-4, a variant of exendin comprising 1-5 deletions at positions 34-39 or a Lys at position 40 having a lipophilic substituent (LS), a glucagon-like peptide (GLP-1) (7-36) or GLP-1 (7-37) substituted by D-Ala, Gly or alpha-amino isobutyric acid for Ala at position 8 or LS, or a sequence (Z), is new. (Z) is a peptide sequence of 4-20 amino acids covalently bound to the variant. Each amino acid in (Z) is selected from A, L, S, T, Y, N, Q, D, G, K, R, H, M, Orn, and amino acid units of formula (I) -NH-C(R1)(R2)-C(=O)-.
R1 and R2 = independently, H, C1-6-alkyl, phenyl and phenyl-methyl, where C1-6-alkyl is optionally substituted with 1-3 substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenylmethyl are optionally substituted with 1-3 substituents selected from C1-6-alkyl, C2-6-alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy; and
R1 and R2 = together with the carbon atom to which they are bound from a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid or its salt, or the C-terminal amide of (I) with the proviso that X is not exendin-4 or exendin-3.
INDEPENDENT CLAIMS are also included for the following:
(1) a pharmaceutically active conjugate (Ia) of (I), for use in therapy;
(2) a variant (II) of a parent exendin, where the parent exendin has an amino acid sequence having at least an 90 % homology to exendin-4, the variant lowers the blood glucose level and binds to a GLP-1 receptor in a mammal and has 1-5 deletions at positions 34-38, or a Lys at position 40 having LS bound to the epsilon-amino group of Lys through an amide bond;
(3) a pharmaceutical composition (PC) comprising (II);
(4) producing (I) or (II), comprising:
(a) introducing a nucleic acid sequence encoding (II) or (I), and a selectable marker contained within a nucleic acid construct or a vector, into a host cell to obtain a recombinant host cell;
(b) selecting the recombinant host cell;
(c) culturing the recombinant host cells under conditions permitting the production of the polypeptide sequence;
(d) isolating the polypeptide sequence from the culture; and
(e) optionally cleaving the polypeptide sequence with a protease;
(5) a polypeptide sequence (III) encoding (I) having a natural polypeptide sequence; and
(6) increasing the plasma half life of exendin-4 or its variants by linking a polypeptide sequence of preferably 6 lysine residues, through a peptide bond to the C-terminal of the exendin-4 or its variant.
