2 research outputs found
A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases
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
Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration
Polyglutamine diseases are a set
of progressive neurodegenerative
disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective
therapeutics that can counteract the polyglutamine neurotoxicity.
Two peptidylic inhibitors, QBP1 and P3, targeting the protein and
RNA toxicities, respectively, have been previously demonstrated by
us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy
has never been investigated in vivo in mammals. The current study
aims to (a) develop a brain-targeting delivery system for both QBP1
and L1P3V8 (a lipidated variant of P3 with improved stability) and
(b) evaluate their therapeutic effects on the R6/2 transgenic mouse
model of polyglutamine disease. Compared with intravenous administration,
intranasal administration of QBP1 significantly increased its brain-to-plasma
ratio. In addition, employment of a chitosan-containing in situ gel
for the intranasal administration of QBP1 notably improved its brain
concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation
of QBP1 and L1P3V8 in mice found no interference on the brain uptake
of each other. Subsequent efficacy evaluation of 4-week daily QBP1
(16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment
in the R6/2 mice demonstrated a significant improvement on the motor
coordination and explorative behavior of the disease mice, together
with a full suppression on the RNA- and protein-toxicity markers in
their brains. In summary, the current study developed an efficient
intranasal cotreatment of the two peptidylic inhibitors, QBP1 and
L1P3V8, for their brain-targeting, and such a novel therapeutic strategy
was found to be effective on a transgenic polyglutamine disease mouse
model