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A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases.

A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases.

Authors :
Zhang Q
Yang M
Sørensen KK
Madsen CS
Boesen JT
An Y
Peng SH
Wei Y
Wang Q
Jensen KJ
Zuo Z
Chan HYE
Ngo JCK
Source :
Scientific reports [Sci Rep] 2017 Sep 21; Vol. 7 (1), pp. 12077. Date of Electronic Publication: 2017 Sep 21.
Publication Year :
2017

Abstract

Polyglutamine (PolyQ) diseases are progressive neurodegenerative disorders caused by both protein- and RNA-mediated toxicities. We previously showed that a peptidyl inhibitor, P3, which binds directly to expanded CAG RNA can inhibit RNA-induced nucleolar stress and suppress RNA-induced neurotoxicity. Here we report a N-acetylated and C-amidated derivative of P3, P3V8, that showed a more than 20-fold increase in its affinity for expanded CAG RNA. The P3V8 peptide also more potently alleviated expanded RNA-induced cytotoxicity in vitro, and suppressed polyQ neurodegeneration in Drosophila with no observed toxic effects. Further N-palmitoylation of P3V8 (L1P3V8) not only significantly improved its cellular uptake and stability, but also facilitated its systemic exposure and brain uptake in rats via intranasal administration. Our findings demonstrate that concomitant N-acetylation, C-amidation and palmitoylation of P3 significantly improve both its bioactivity and pharmacological profile. L1P3V8 possesses drug/lead-like properties that can be further developed into a lead inhibitor for the treatment of polyQ diseases.

Details

Language :
English
ISSN :
2045-2322
Volume :
7
Issue :
1
Database :
MEDLINE
Journal :
Scientific reports
Publication Type :
Academic Journal
Accession number :
28935901
Full Text :
https://doi.org/10.1038/s41598-017-11695-y