Indiana University

Bin Yang

Richard Dennis DiMarchi

David L Smiley

Brian Finan

Chenguang Ouyang

Provided herein are glucagon superfamily peptides conjugated with NHR ligands that are capable of acting at a nuclear hormone receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.

Glucagon superfamily peptides exhibiting nuclear hormone receptor activity

Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.

Glucagon/GLP-1 receptor co-agonists

Glucagon antagonists are provided which comprise amino acid substitutions and/or chemical modifications to glucagon sequence. In one embodiment, the glucagon antagonists comprise a native glucagon peptide that has been modified by the deletion of the first two to five amino acid residues from the N-terminus and (i) an amino acid substitution at position 9 (according to the numbering of native glucagon) or (ii) substitution of the Phe at position 6 (according to the numbering of native glucagon) with phenyl lactic acid (PLA). In another embodiment, the glucagon antagonists comprise the structure A-B-C as described herein, wherein A is PLA, an oxy derivative thereof, or a peptide of 2-6 amino acids in which two consecutive amino acids of the peptide are linked via an ester or ether bond.

Glucagon antagonists

Glucagon analogs are disclosed that exhibit both glucagon antagonist and GLP-1 agonist activity. In one embodiment, the glucagon antagonist/GLP-1 agonist comprises a modified amino acid sequence of native glucagon, in which the first one to five N-terminal amino acids of native glucagon is deleted and in which the alpha helix is stabilized.

Peptide compounds exhibiting glucagon antagonist and GLP-1 agonist activity

Provided herein are glucagon superfamily peptides conjugated with GR ligands that are capable of acting at a glucocorticoid receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.

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Bloomington, IN, United States of America

Bin Yang