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Rationally designed helical peptidomimetics disrupt alpha–synuclein fibrillation

Rationally designed helical peptidomimetics disrupt alpha–synuclein fibrillation
Rationally designed helical peptidomimetics disrupt alpha–synuclein fibrillation
Misfolding of the human protein alpha-synuclein results in toxic fibrils and the aggregation of Lewy bodies, which are a hallmark of Parkinson’s disease in brain tissue. Here we disclose a supramolecular approach where peptidomimetics are rationally designed and pre-organised to recognize the surface of native helical, pre-fibrillar, alpha-Syn by forming complementary contacts with key patches of protein surface composed of charged and hydrophobic residues. Under lipid-catalyzed conditions the mimetics slow the rate of aggregation (thioflavin-T assay) and disrupt the misfolding pathway (electron microscopy of aggregates). This hypothesis is supported by comparison with a series of negative control compounds and with circular dichroism experiments. Given the approach relies on selective recognition of both amino acid sequence and conformation (helical secondary structure) there is potential to develop these compounds as tools to unravel the currently intractable structure-function relationships of (i) missense mutation, and (ii) amyloid polymorphism with disease pathogenesis.
PROTEIN, misfolding, peptidomimetic, rational design, structure guided
1359-7345
5132-5135
Bavinton, Clementine, Ella
7fb75a01-95f8-4eeb-8c1b-0d566c0d71be
Sternke-Hoffmann, Rebecca
d4cff382-a536-432a-bc97-d3b81b043da8
Yamashita, Tohru
e46eec97-5f8d-4db1-96cb-68f0392376b9
Knipe, Peter
af1bf652-e106-4f3c-9abd-cdae0e075c72
Hamilton, Andrew D.
a4746abb-aa88-4497-b94c-b70066c57769
Luo, Jinghui
39a1708f-6cf2-437d-a9a2-0d6eaf092c86
Thompson, Sam
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Bavinton, Clementine, Ella
7fb75a01-95f8-4eeb-8c1b-0d566c0d71be
Sternke-Hoffmann, Rebecca
d4cff382-a536-432a-bc97-d3b81b043da8
Yamashita, Tohru
e46eec97-5f8d-4db1-96cb-68f0392376b9
Knipe, Peter
af1bf652-e106-4f3c-9abd-cdae0e075c72
Hamilton, Andrew D.
a4746abb-aa88-4497-b94c-b70066c57769
Luo, Jinghui
39a1708f-6cf2-437d-a9a2-0d6eaf092c86
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1

Bavinton, Clementine, Ella, Sternke-Hoffmann, Rebecca, Yamashita, Tohru, Knipe, Peter, Hamilton, Andrew D., Luo, Jinghui and Thompson, Sam (2022) Rationally designed helical peptidomimetics disrupt alpha–synuclein fibrillation. Chemical Communications, 58 (33), 5132-5135. (doi:10.1039/D2CC00212D).

Record type: Article

Abstract

Misfolding of the human protein alpha-synuclein results in toxic fibrils and the aggregation of Lewy bodies, which are a hallmark of Parkinson’s disease in brain tissue. Here we disclose a supramolecular approach where peptidomimetics are rationally designed and pre-organised to recognize the surface of native helical, pre-fibrillar, alpha-Syn by forming complementary contacts with key patches of protein surface composed of charged and hydrophobic residues. Under lipid-catalyzed conditions the mimetics slow the rate of aggregation (thioflavin-T assay) and disrupt the misfolding pathway (electron microscopy of aggregates). This hypothesis is supported by comparison with a series of negative control compounds and with circular dichroism experiments. Given the approach relies on selective recognition of both amino acid sequence and conformation (helical secondary structure) there is potential to develop these compounds as tools to unravel the currently intractable structure-function relationships of (i) missense mutation, and (ii) amyloid polymorphism with disease pathogenesis.

Text
22-03-27 aSyn mimetics accepted - Accepted Manuscript
Restricted to Repository staff only until 26 March 2023.
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More information

Accepted/In Press date: 26 March 2022
e-pub ahead of print date: 30 March 2022
Published date: 21 April 2022
Keywords: PROTEIN, misfolding, peptidomimetic, rational design, structure guided

Identifiers

Local EPrints ID: 456397
URI: http://eprints.soton.ac.uk/id/eprint/456397
ISSN: 1359-7345
PURE UUID: a12dfab8-dfe4-4cc9-9f8f-52cfe71962eb
ORCID for Sam Thompson: ORCID iD orcid.org/0000-0001-6267-5693

Catalogue record

Date deposited: 27 Apr 2022 15:45
Last modified: 23 Jul 2022 02:12

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Contributors

Author: Clementine, Ella Bavinton
Author: Rebecca Sternke-Hoffmann
Author: Tohru Yamashita
Author: Peter Knipe
Author: Andrew D. Hamilton
Author: Jinghui Luo
Author: Sam Thompson ORCID iD

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