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The impact of lipidation on the self-assembly and bioactivity of the gastrointestinal peptide hormone PYY3-36

Hutchinson, J. (2019) The impact of lipidation on the self-assembly and bioactivity of the gastrointestinal peptide hormone PYY3-36. PhD thesis, University of Reading

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Abstract/Summary

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.

Item Type:Thesis (PhD)
Thesis Supervisor:Hamley, I.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:89057

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