A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases. / Zhang, Qian; Yang, Mengbi; Sørensen, Kasper K.; Madsen, Charlotte S.; Boesen, Josephine T.; An, Ying; Peng, Shao Hong; Wei, Yuming; Wang, Qianwen; Jensen, Knud J.; Zuo, Zhong; Chan, Ho Yin Edwin; Ngo, Jacky Chi Ki.
I: Scientific Reports, Bind 7, Nr. 1, 12077, 2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases
AU - Zhang, Qian
AU - Yang, Mengbi
AU - Sørensen, Kasper K.
AU - Madsen, Charlotte S.
AU - Boesen, Josephine T.
AU - An, Ying
AU - Peng, Shao Hong
AU - Wei, Yuming
AU - Wang, Qianwen
AU - Jensen, Knud J.
AU - Zuo, Zhong
AU - Chan, Ho Yin Edwin
AU - Ngo, Jacky Chi Ki
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-017-11695-y
DO - 10.1038/s41598-017-11695-y
M3 - Journal article
C2 - 28935901
AN - SCOPUS:85029869568
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 12077
ER -
ID: 184293416