Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold

Wang, Conan K., Northfield, Susan E., Huang, Yen-Hua, Ramos, Mariana C. and Craik, David J. (2016) Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold. European Journal of Medicinal Chemistry, 109 342-349. doi:10.1016/j.ejmech.2016.01.006

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Author Wang, Conan K.
Northfield, Susan E.
Huang, Yen-Hua
Ramos, Mariana C.
Craik, David J.
Title Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1768-3254
Publication date 2016-02-15
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2016.01.006
Open Access Status File (Author Post-print)
Volume 109
Start page 342
End page 349
Total pages 8
Place of publication Issy les Moulineaux, Cedex, France
Publisher Elsevier Masson
Language eng
Subject 3004 Pharmacology
3002 Drug Discovery
1605 Organic Chemistry
Abstract Disulfide-rich macrocyclic peptides are emerging as versatile scaffolds for the development of stable biochemical tools. This potential is due to the combination of their structural stability and range of bioactivities. Here, we explored the activity of these peptides on fibril growth of the hexapeptide Ac-VQIVYK-NH2 (AcPHF6), which is a tau-derived peptide that has been widely used to understand the pathological mechanism of numerous tauopathies, including Alzheimer's disease. Of the cyclic peptides tested, SFTI-1 and kB1 showed an inherent ability to inhibit AcPHF6 fibril formation. Using an end-capping strategy and combining it with a molecular grafting approach, we demonstrated that SFTI-1 could be used as a starting point to design more potent fibril inhibitors. We further identified chemical and structural features of SFTI-1 and its analogues that underpin their inhibitory activity. The ability to inhibit fibril growth using the strategy employed herein supports the 'steric zipper' model of AcPHF6 fibril formation and shows that naturally-occurring cyclic peptides have potential as drug leads or molecular probes for understanding fibril formation.
Keyword Aggregation
Cyclic peptide
Disulfide bond
Molecular grafting
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 6 times in Thomson Reuters Web of Science Article | Citations
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