Reversible PEGylation of peptide YY3-36 prolongs its inhibition of food intake in mice.
Administration of peptide YY(3-36) (PYY(3-36)) to fasting humans or mice shortly before re-feeding effectively reduced their food intake, but PYY(3-36) exhibited a functional half-life of only approximately 3 h. Attachment of poly(ethylene glycol) to proteins and peptides (PEGylation) prolongs their half-life in vivo, but completely inactivated PYY(3-36). We developed a reversibly PEGylated PYY(3-36) derivative by coupling it to a 40 kDa PEG through a spontaneously cleavable linker. The resulting conjugate (PEG(40)-FMS-PYY(3-36)) gradually released unmodified PYY(3-36) in vivo, exhibiting an eightfold increase in its functional half-life, to approximately 24h. This long-acting PYY(3-36) pro-drug may serve as an effective means for controlling food intake in humans.
Shechter
Yoram
Y
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Tsubery
Haim
H
Mironchik
Marina
M
Rubinstein
Menachem
M
Fridkin
Mati
M
D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects*; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments; D019894:Peptide YY / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
D010446:Peptide Fragments; D019894:Peptide YY; C061785:peptide YY (3-36); D011092:Polyethylene Glycols