Peptide YY (PYY) is a gut hormone belonging to the pancreatic polypeptide (PP) family,
and is released by the L-cells of the gastrointestinal tract following food intake. There
are two main endogenous forms: PYY1-36 and PYY3-36, with the latter having a high
selectivity for the Y2-receptor which is associated with reduced food intake. The use of
PYY3-36 as an anti-obesity and type II diabetes drug is therefore of great interest.
Peptide hormones have short circulating half-lives; therefore it is of high importance to
develop a strategy to overcome this for the development of peptide drugs. The use of
lipidation is a promising method as it allows the peptide to bind to serum albumin,
increasing molecular weight and thus reducing renal filtration.
In this thesis the impact of lipidation, and the position of lipidation on the self-assembly
of PYY3-36 and various truncated derivatives are investigated. A wide range of physical
characterisation techniques are employed to understand self-assembly and
aggregation. Some cytotocompatibility studies using MTT assays on human colorectal
cancer cells are also carried out in order to understand cytotoxicity.
It was apparent throughout the project that lipidation significantly impacted the selfassembly,
by helping to drive aggregation as a result of the increased amphiphilicity
caused by the addition of the lipid chain, which in this case was a palmitoyl chain. The
full PYY3-36 peptide and the lipidated derivatives had predominantly α-helical secondary
structures. They differed largely when they aggregated however, with the native peptide
being mostly monomers with some nanotapes, and the lipidated peptides having micelle
and fibril conformations depending on pH. In addition to this the lipidated peptides
formed gels under specific conditions whereas the native peptide did not.
Investigations into the truncated peptide fragments further enhanced the impact of
lipidation, where the lipidated fragments had micelle and fibril conformation, whereas
the native fragments did not aggregate at all. Cytocompatibility studies found the
lipidated peptides to be cytotoxic at concentrations above the cmc, suggesting that
aggregation causes the peptides to become cytotoxic
