title: Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation.
abstract: The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.
authors.affiliation: Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Leipzig, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bellmann-Sickert
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elling
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.forename: Paul B
authors.initials: PB
authors.lastname: Little
authors.forename: Karsten
authors.initials: K
authors.lastname: Lundgren
authors.forename: Lars-Ole
authors.initials: LO
authors.lastname: Gerlach
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D006801:Humans; D006868:Hydrolysis; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010191:Pancreatic Polypeptide / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D008055:Lipids; D010191:Pancreatic Polypeptide