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.

Native chemical ligation derived method for recombinant peptide/protein C-terminal amidation.

C-terminal amidation is often a requisite structural feature for peptide hormone bio-activity. We report a chemical amidation method that converts peptide/protein thioesters into their corresponding C-terminal amides. The peptide/protein thioester is treated with 1-(2,4-dimethoxyphenyl)-2-mercaptoethyl auxiliary (1b) in a native chemical ligation (NCL) reaction to form an intermediate, which upon removal of the auxiliary with TFA, yields the peptide/protein amide.