Novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action.

The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu(14)]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold.

Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids.

Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid.

Bifunctional PEGylated exenatide-amylinomimetic hybrids to treat metabolic disorders: an example of long-acting dual hormonal therapeutics.

Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy.

A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.

Aim: Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794.

Methods: AC163794 was synthesized by solid-phase peptide synthesis.

Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents.

Aims: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches.

Methods: Acute food consumption was measured in overnight fasted male wild-type (WT) and melanocortin-4 receptor (MC-4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO).