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Conformation and aggregation of selectively PEGylated and lipidated gastric peptide hormone human PYY3–36

Castelletto, V., Hamley, I. W., Seitsonen, J., Ruokolainen, J., Harris, G., Bellmann-Sickert, K. and Beck-Sickinger, A. G. (2018) Conformation and aggregation of selectively PEGylated and lipidated gastric peptide hormone human PYY3–36. Biomacromolecules, 19 (11). pp. 4320-4332. ISSN 1525-7797

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To link to this item DOI: 10.1021/acs.biomac.8b01209

Abstract/Summary

The gastric peptide hormone human PYY3–36 is a target for the development of therapeutics, especially for treatment of obesity. The conformation and aggregation behavior of PEGylated and lipidated derivatives of this peptide are examined using a combination of fluorescence dye assays, circular dichroism (CD) spectroscopy, analytical ultracentrifugation (AUC) measurements, small-angle X-ray scattering (SAXS) and cryogenic-transmission electron microscopy (cryo-TEM). The behavior of two PYY3–36 derivatives lipidated (with octyl chains) in different positions is compared to that of two derivatives with PEG attached at different residues and to that of the native peptide. We find that, unexpectedly, PYY3–36 forms amyloid fibril structures above a critical aggregation concentration. Formation of these structures is suppressed by PEGylation or lipidation. PEGylation significantly reduces the (reversible) loss of α-helix content observed on heating PYY3–36. The PEG conjugates form mainly monomeric structures in solution- coiled-coil formation, and other aggregation presumably being sterically hindered by swollen PEG chains. However, some small aggregates are detected by AUC. In complete contrast, both of the two lipidated peptides show the formation of spherical micelle-like structures which are small oligomeric aggregates. Our findings show that PEGylation and lipidation are complementary strategies to tune the conformation and aggregation of the important gastric peptide hormone human PYY3–36.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:79850
Uncontrolled Keywords:Materials Chemistry, Bioengineering, Polymers and Plastics, Biomaterials
Publisher:American Chemical Society

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