Abstract: Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

Abstract: Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

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

Abstract: Disclosed herein are insulin analog conjugates comprising an insulin agonist covalently linked to an insulin antagonist peptide. The conjugates are high potency insulin agonists but with decreased maximal activity relative to the maximal activity of native insulin.

Abstract: Glucagon peptides with increased GIP activity are provided, optionally with GLP-1 and/or glucagon activity. In some embodiments, C-terminally extended glucagon peptides comprising an amino acid sequence substantially similar to native glucagon are provided herein.

Abstract: 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.

Abstract: Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half-lives and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Disclosed herein are insulin agonist peptides conjugated to incretins wherein the incretin-insulin conjugate has agonist activity at the insulin receptor and the corresponding incretin receptor, and stimulates weight loss in an individual administered the compound.

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

Abstract: Compositions and formulations comprising insulin or insulin analogs comprising a carboxy terminal portion (CTP) peptide comprising amino acids 112-118 to 145 of the beta subunit of human chorionic gonadotropin (hCG?) or a partial variant thereof that includes at least one O-glycosylation site of the CTP peptide, wherein the CTP peptide of the CTP peptide-based insulin or insulin analog is O-glycosylated are described. In particular embodiments, the O-glycosylated insulin analogs are produced in vivo and in further embodiments, the O-glycosylated CTP-based insulin analogs comprise predominantly mannotriose and mannotetrose O-glycans or predominantly mannose O-glycans.

Abstract: Disclosed herein are insulin analog dimers having unique insulin receptor agonist activity based on insulin polypeptide sequences, the site of dimerization and the length of the dimerization linker that connects the two insulin polypeptides. In accordance with one embodiment the first and second insulin polypeptide are independently a two chain insulin analog or a single chain analog and the first and second insulin polypeptides are linked to one another via a B29-B29?, B1-C8, B1-B1 or C8-C8 linkage.

Abstract: Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

Abstract: Insulin analogs comprising a non-native glycosylation site sequence are provided having high potency and specificity for the insulin receptor. In one embodiment a peptide sequence of greater than 18 amino acids is used as a linking moiety to link human insulin A and B chains, or analogs or derivatives thereof, to provide high potency single chain insulin analogs. In one embodiment the linking moiety comprises one or more glycosylation sites. Also disclosed are prodrug and conjugate derivatives of the insulin analogs.

Abstract: Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

Abstract: Provided herein are peptide combinations comprising a GIP agonist peptide and a glucagon antagonist peptide. In some embodiments, the peptide combination is provided as a composition, e.g., a pharmaceutical composition, while in other embodiments, the peptide combination is provided as a kit. In yet other embodiments, the peptide combination is provided as a conjugate, e.g., a fusion peptide, a heterodimer. In specific aspects, the GIP agonist peptide is an analog of native human glucagon. In specific aspects, the glucagon antagonist peptide is an analog of native human glucagon. In some embodiments, the GIP agonist peptide is covalently attached to the glucagon antagonist peptide via a linker. Method of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the peptide compositions described herein are further provided.

Abstract: Herein is reported a fusion polypeptide comprising i) one, two, three or four incretin receptor ligand polypeptides, and ii) one human immunoglobulin Fc-region, wherein at least one of the incretin receptor ligand polypeptides comprises an amino acid that is covalently conjugated to a lipid, and wherein each of the one, two, three or four incretin receptor ligand polypeptides is covalently conjugated by a peptide bond to a terminus of the human immunoglobulin Fc-region, whereby to each terminus of the human immunoglobulin Fc-region only a single incretin receptor ligand polypeptide is conjugated.

Abstract: Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

Abstract: Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming lactam bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, substitution of carboxy terminal amino acids, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).

Abstract: Methods are provided for administering an extended half-life GLP-1/GIP coagonist peptide to a patient in need thereof for reducing weight gain, inducing weight loss, treating hyperglycemia, reducing blood glucose levels, or normalizing blood glucose levels in said patient.

Abstract: A non-enzymatically self cleaving dipeptide element is provided that can be linked to known medicinal agents via an amide bond. The dipeptide will spontaneously be cleaved from the medicinal agent under physiological conditions through a reaction driven by chemical instability. Accordingly, the dipeptide element provides a means of linking various compounds to known medicinal agents wherein the compounds are subsequently released from the medicinal agent after a predetermined time of exposure to physiological conditions. For example, the dipeptide can be linked to an active site of a drug to form a prodrug and/or the dipeptide may comprise a depot polymer to sequester an injectable composition comprising the complex at the point of administration.