The developed world is currently in the grip of an obesity epidemic. As a result, there
is much ongoing research into the development of an effective anti-obesity agent.
Peptide YY (PYY) is a 36 amino acid gastro-intestinal hormone released post-prandially
by L-cells in the gastro-intestinal tract in proportion to the calorie content
of a meal. The predominant form of the hormone found in circulation is the truncated
PYY(3-36). Administration of PYY(3-36) at physiological doses to humans has been
shown to reduce food intake. However, due to enzymatic degradation these effects are
short lived, reducing the hormone’s utility as an anti-obesity pharmaceutical agent. A
series of analogues of PYY(3-36) were designed either with amino acid substitutions
in specific parts of the peptide sequence and/or with chemical modifications to the
native sequence with the aim of increasing resistance to enzymatic activity whilst
retaining or even enhancing the peptide’s bioactivity. The analogues were tested for
resistance to degradation by different proteolytic enzymes in comparison to natural
PYY(3-36). Their affinity to the Y2 receptor, for which PYY(3-36) is a natural
agonist was then investigated. Finally, the effects of peripheral administration of
selected analogues on food intake in overnight fasted mice were investigated. These
studies suggest that PYY(3-36) analogues may be a useful approach for the treatment
of obesity, but further development work is required.