A novel long-acting selective neuropeptide Y2 receptor polyethylene glycol-conjugated peptide agonist reduces food intake and body weight and improves glucose metabolism in rodents.

Selective activation of the neuropeptide Y (NPY)2 receptor to suppress appetite provides a promising approach to obesity management. A selective NPY2 polyethylene glycol-conjugated (PEGylated) peptide agonist is described that consists of a peptide core corresponding to residues 13 to 36 of human peptide YY (PYY) and a nonpeptidic moiety (2-mercaptonicotinic acid) at the peptide N terminus that is derivatized with 20-kDa monomethoxypolyethylene glycol. The PEGylated peptide elicits a dose-dependent reduction in food intake in lean C57BL/6 mice and Wistar rats that persists for 72 and 48 h, respectively.

Novel selective neuropeptide Y2 receptor PEGylated peptide agonists reduce food intake and body weight in mice.

Selective activation of the NPY2 receptor to suppress appetite provides an approach to obesity management. Selective NPY2 PEGylated peptide agonists are described that consist of a peptide core corresponding to residues 25-36 of PYY and a nonpeptidic moiety at the peptide N-terminus that contributes to in vitro potency and in vivo efficacy and provides a PEGylation site. The lead peptide elicits a dose-dependent reduction of food intake in lean mice and of food intake, body weight, and fat mass in DIO mice.

A long-acting selective neuropeptide Y2 receptor PEGylated peptide agonist reduces food intake in mice.

Activation of the NPY2 receptor to reduce appetite while avoiding activation of the NPY1 and NPY5 receptors that stimulate feeding provides a pharmaceutical approach to modulate food intake. The naturally occurring peptide and development candidate PYY(3-36) is a non-selective NPY1, NPY2, and NPY5 agonist of limited in vivo duration of action. N-terminal modification with 20 kDa PEG of a selective NPY2 receptor agonist peptide results in a long-acting agent that outperforms PYY(3-36) in reducing food intake in mice.