Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation
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Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation. / Bellmann-Sickert, Kathrin; Elling, Christian E; Madsen, Andreas N; Little, Paul B; Lundgren, Karsten; Gerlach, Lars-Ole; Bergmann, Ralf; Holst, Birgitte; Schwartz, Thue W; Beck-Sickinger, Annette G.
I: Journal of Medicinal Chemistry, Bind 54, Nr. 8, 2011, s. 2658-67.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2011
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
VL - 54
SP - 2658
EP - 2667
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -
ID: 33802418