Reversible PEGylation of peptide YY3-36 prolongs its inhibition of food intake in mice

Administration of peptide YY3-36 (PYY3-36) to fasting humans or mice shortly before re-feeding effectively reduced their food intake, but PYY3-36 exhibited a functional half-life of only ∼3 h. Attachment of poly(ethylene glycol) to proteins and peptides (PEGylation) prolongs their half-life in vivo, but completely inactivated PYY3-36. We developed a reversibly PEGylated PYY3-36 derivative by coupling it to a 40 kDa PEG through a spontaneously cleavable linker. The resulting conjugate (PEG40–FMS–PYY3-36) gradually released unmodified PYY3-36 in vivo, exhibiting an eightfold increase in its functional half-life, to ∼24 h. This long-acting PYY3-36 pro-drug may serve as an effective means for controlling food intake in humans.