CD71+ erythroid suppressor cells impair adaptive immunity against Bordetella pertussis

Polyglutamine (PolyQ) diseases are progressive neurodegenerative disorders caused by both proteinand 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 afnity 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 efects. Further N-palmitoylation of P3V8 (L1P3V8) not only signifcantly improved its cellular uptake and stability, but also facilitated its systemic exposure and brain uptake in rats via intranasal administration. Our fndings demonstrate that concomitant N-acetylation, C-amidation and palmitoylation of P3 signifcantly improve both its bioactivity and pharmacological profle. L1P3V8 possesses drug/lead-like properties that can be further developed into a lead inhibitor for the treatment of polyQ diseases.