US 5,545,618 AGranted

GLP-1 analogs useful for diabetes treatment

OwnerDouglas I. Buckley, Joel F. Habener +2inventors

InventorsDouglas I. Buckley, Joel F. Habener, Joanne B. Mallory, Svetlana Mojsov

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Abstract

The invention provides effective analogs of the active GLP-1 peptides, 7-34, 7-35, 7-36, and 7-37, which have improved characteristics for treatment of diabetes Type II. These analogs have amino acid substitutions at positions 7-10 and/or are truncated at the C-terminus and/or contain various other amino acid substitutions in the basic peptide. The analogs may either have an enhanced capacity to stimulate insulin production as compared to glucagon or may exhibit enhanced stability in plasma as compared to GLP-1 (7-37) or both. Either of these properties will enhance the potency of the analog as a therapeutic. Analogs having D-amino acid substitutions in the 7 and 8 positions and/or N-alkylated or N-acylated amino acids in the 7 position are particularly resistant to degradation in vivo.

Claims14

Dependent claims

A peptide which is more potent than glucagon in stimulating insulin release from islet cells, said peptide consisting of labeled or unlabeled GLP-1(7-34), GLP-1(7-35), GLP-1(7-36), or GLP-1(7-37) or the C-terminal amide form thereof, having at least one modification selected from the group consisting of:

(a) substitution of a neutral amino acid, arginine, or a D form of lysine for lysine at position 26 and/or 34 and/or a neutral amino acid, lysine, or a D form of arginine for arginine at position 36;
(b) substitution of an oxidation-resistant amino acid for tryptophan at position
(c) substitution according to at least one of:
Y for V at position 16;
K for S at position 18;
D for E at position 21;
S for G at position 22;
R for Q at position 23;
R for A at position 24;
and
Q for K at position 26;
(d) a substitution consisting of at least one of:
an alternative small neutral amino acid for A at position 8;
an alternative acidic amino acid or neutral amino acid for E at position 9;
an alternative neutral amino acid for G at position 10;
and
an alternative acidic amino acid for D at position 15;
and
(c) substitution of an alternative neutral amino acid or the D or N-acylated or alkylated form of histidine for histidine at position 7
wherein for (a), (b), (d) and (e), the substituted amino acids can optionally be in the D form and the amino acids substituted at position 7 can optionally be in the N-acylated or N-alkylated form.

17 more elements

Dependencies are inferred from the claim text.