Photocontrol of the β-Hairpin Polypeptide Structure through an Optimized Azobenzene-Based Amino Acid Analogue

Raffaella Parlato, Jana Volarić, Alessia Lasorsa, Mahdi Bagherpoor Helabad, Piermichele Kobauri, Greeshma Jain, Markus S Miettinen, Ben L Feringa*, Wiktor Szymanski*, Patrick C A van der Wel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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A family of neurodegenerative diseases, including Huntington's disease (HD) and spinocerebellar ataxias, are associated with an abnormal polyglutamine (polyQ) expansion in mutant proteins that become prone to form amyloid-like aggregates. Prior studies have suggested a key role for β-hairpin formation as a driver of nucleation and aggregation, but direct experimental studies have been challenging. Toward such research, we set out to enable spatiotemporal control over β-hairpin formation by the introduction of a photosensitive β-turn mimic in the polypeptide backbone, consisting of a newly designed azobenzene derivative. The reported derivative overcomes the limitations of prior approaches associated with poor photochemical properties and imperfect structural compatibility with the desired β-turn structure. A new azobenzene-based β-turn mimic was designed, synthesized, and found to display improved photochemical properties, both prior and after incorporation into the backbone of a polyQ polypeptide. The two isomers of the azobenzene-polyQ peptide showed different aggregate structures of the polyQ peptide fibrils, as demonstrated by electron microscopy and solid-state NMR (ssNMR). Notably, only peptides in which the β-turn structure was stabilized (azobenzene in the cis configuration) closely reproduced the spectral fingerprints of toxic, β-hairpin-containing fibrils formed by mutant huntingtin protein fragments implicated in HD. These approaches and findings will enable better deciphering of the roles of β-hairpin structures in protein aggregation processes in HD and other amyloid-related neurodegenerative diseases.

Original languageEnglish
Pages (from-to)2062–2071
Number of pages10
JournalJournal of the American Chemical Society
Issue number3
Early online date16-Jan-2024
Publication statusPublished - 24-Jan-2024


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