Control of Peptide Aggregation and Fibrillation by Physical PEGylation

Show full item record



Permalink

http://hdl.handle.net/10138/326464

Citation

Ambrosio , E , Podmore , A , dos Santos , A L G , Magarkar , A , Bunker , A , Caliceti , P , Mastrotto , F , van der Walle , C F & Salmaso , S 2018 , ' Control of Peptide Aggregation and Fibrillation by Physical PEGylation ' , Biomacromolecules , vol. 19 , no. 10 , pp. 3958-3969 . https://doi.org/10.1021/acs.biomac.8b00887

Title: Control of Peptide Aggregation and Fibrillation by Physical PEGylation
Author: Ambrosio, Elena; Podmore, Adrian; dos Santos, Ana L. Gomes; Magarkar, Aniket; Bunker, Alex; Caliceti, Paolo; Mastrotto, Francesca; van der Walle, Christopher F.; Salmaso, Stefano
Other contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy


Date: 2018-10
Language: eng
Number of pages: 12
Belongs to series: Biomacromolecules
ISSN: 1525-7797
DOI: https://doi.org/10.1021/acs.biomac.8b00887
URI: http://hdl.handle.net/10138/326464
Abstract: Peptide therapeutics have the potential to self-associate, leading to aggregation and fibrillation. Noncovalent PEGylation offers a strategy to improve their physical stability; an understanding of the behavior of the resulting polymer/ peptide complexes is, however, required. In this study, we have performed a set of experiments with additional mechanistic insight provided by in silico simulations to characterize the molecular organization of these complexes. We used palmitoylated vasoactive intestinal peptide (VIP-palm) stabilized by methoxy-poly(ethylene glycol)(skDa)-cholane (PEG-cholane) as our model system. Homogeneous supramolecular assemblies were found only when complexes of PEG-cholane/VIP-palm exceeded a molar ratio of 2:1; at and above this ratio, the simulations showed minimal exposure of VIP-palm to the solvent. Supramolecular assemblies formed, composed of, on average, 9-11 PEG-cholane/VIP-palm complexes with 2:1 stoichiometry. Our in silico results showed the structural content of the helical conformation in VIP-palm increases when it is complexed with the PEG-cholane molecule; this behavior becomes yet more pronounced when these complexes assemble into larger supramolecular assemblies. Our experimental results support this: the extent to which VIP-palm loses helical structure as a result of thermal denaturation was inversely related to the PEG-cholane:VIP-palm molar ratio. The addition of divalent buffer species and increasing the ionic strength of the solution both accelerate the formation of VIP-palm fibrils, which was partially and fully suppressed by 2 and >4 mol equivalents of PEG-cholane, respectively. We conclude that the relative freedom of the VIP-palm backbone to adopt nonhelical conformations is a key step in the aggregation pathway.
Subject: VASOACTIVE-INTESTINAL-PEPTIDE
MOLECULAR-DYNAMICS SIMULATION
CIRCULAR-DICHROISM
PROTEIN AGGREGATION
THIOFLAVIN-T
PEG-CHOLANE
MODEL
DELIVERY
INSULIN
TEMPERATURE
1182 Biochemistry, cell and molecular biology
116 Chemical sciences
317 Pharmacy
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Ambrosio_et_al.pdf 1.916Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record