Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation

TY - JOUR

T1 - Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation

AU - Bellmann-Sickert, Kathrin

AU - Elling, Christian E

AU - Madsen, Andreas N

AU - Little, Paul B

AU - Lundgren, Karsten

AU - Gerlach, Lars-Ole

AU - Bergmann, Ralf

AU - Holst, Birgitte

AU - Schwartz, Thue W

AU - Beck-Sickinger, Annette G

PY - 2011/4/28

Y1 - 2011/4/28

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Biological Availability

KW - Humans

KW - Hydrolysis

KW - Lipids

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Molecular Sequence Data

KW - Pancreatic Polypeptide

KW - Protein Structure, Secondary

KW - Rats

KW - Rats, Wistar

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

U2 - 10.1021/jm101357e

DO - 10.1021/jm101357e

M3 - Journal article

C2 - 21410292

SN - 0022-2623

VL - 54

SP - 2658

EP - 2667

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -