A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases
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AbstractPolyglutamine (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.
Acceptance Date29/08/2017
All Author(s) ListQian Zhang, Mengbi Yang, Kasper K. Sørensen, Charlotte S. Madsen, Josephine T. Boesen, Ying An, Shao Hong Peng, Yuming Wei, Qianwen Wang, Knud J. Jensen, Zhong Zuo, Ho Yin Edwin Chan, Jacky Chi Ki Ngo
Journal nameScientific Reports
Year2017
Month9
Day21
Volume Number7
Pages12077
ISSN2045-2322
eISSN2045-2322
LanguagesEnglish-United States

Last updated on 2021-05-03 at 00:22