RESUMEN
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.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Oligopéptidos/síntesis química , Péptido YY/química , Polietilenglicoles/química , Receptores de Neuropéptido Y/agonistas , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , AMP Cíclico/biosíntesis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Oligopéptidos/química , Oligopéptidos/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Péptido YY/farmacología , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
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. The acetylated peptide, Ac-VPAC2P-PEG, is a selective and potent VPAC2 agonist, resistant to DPPIV proteolysis, and exhibits substantially improved half-life and glucose disposal in rodents. Ac-VPAC2P-PEG has therapeutic potential for diabetes management.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Glucosa/metabolismo , Hipoglucemiantes/síntesis química , Insulina/metabolismo , Péptidos/síntesis química , Receptores de Tipo II del Péptido Intestinal Vasoactivo/agonistas , Acetilación , Animales , Células CHO , Cricetinae , Cricetulus , Semivida , Humanos , Hidrólisis , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Secreción de Insulina , Masculino , Péptidos/química , Péptidos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismoRESUMEN
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. Moreover, the dual modification of N-terminal palmitoylation and C-terminal PEGylation results in a full agonist of comparable potency to native GIP that is stable to DPPIV cleavage. The results provide the basis for the development of long acting, PEGylated GIP, GIP variants, or GIP-based hybrid peptide therapeutics.
