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.

Generation and characterization of a monoclonal IgG antibody to polyethylene glycol.

An IgG mouse monoclonal antibody (10F05) against polyethylene glycol has been generated. The antibody reacts with PEG regardless of the linker used for PEG attachment, and is able to recognize a PEGylated peptide in plasma at concentrations as low as 3 pg/mL. The antibody is readily purified in substantial quantities.

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.

Engineering of a VPAC2 receptor peptide agonist to impart dipeptidyl peptidase IV stability and enhance in vivo glucose disposal.

VPAC2P-PEG is a VPAC2 receptor agonist peptide that acts as a glucose-dependent insulin secretagogue. Proteolysis by DPPIV may contribute to the in vivo clearance of VPAC2P-PEG. Here, the N-terminus of VPAC2P-PEG is modified by N-terminal acetylation to impart DPPIV resistance.

Identification of selective neuropeptide Y2 peptide agonists.

Activation of the NPY2 receptor to reduce appetite while avoiding stimulation of the NPY1 and NPY5 receptors that induce feeding provides a pharmaceutical approach to modulate food intake. The naturally occurring peptide PYY(3-36) is a nonselective NPY1, NPY2, and NPY5 agonist. N-terminal truncation of PYY to abrogate affinity for the NPY1 and NPY5 receptors and subsequent N-terminal modification with aminobenzoic analogs to restore NPY2 receptor potency results in a series of highly selective NPY2 receptor peptide agonists.

Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide.

The effects of PEGylation of glucose-dependent insulinotropic polypeptide (GIP) on potency and dipeptidyl peptidase IV (DPPIV) stability are reported. N-terminal modification of GIP(1-30) with 40 kDa polyethylene glycol (PEG) abrogates functional activity. In contrast, C-terminal PEGylation of GIP(1-30) maintains full agonism and reasonable potency at the GIP receptor and confers a high level of DPPIV resistance.