Expanded Polyglutamine-Binding Peptoid as a Novel Therapeutic Agent for Treatment of Huntington's Disease

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Chemistry & biology (Impact Factor: 6.65). 09/2011; 18(9):1113-25. DOI: 10.1016/j.chembiol.2011.06.010
Source: PubMed


Polyglutamine(polyQ)-expanded proteins are potential therapeutic targets for the treatment of polyQ expansion disorders such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). Here, we used an amino-terminal fragment of a mutant Huntingtin protein (Htt-N-82Q) as bait in an unbiased screen of a 60,000 peptoid library. Peptoid HQP09 was selected from the isolated hits and confirmed as a specific ligand of Htt-N-82Q and Atxn3-77Q mutant proteins in biochemical experiments. We identified three critical residues in the HQP09 sequence that are important for its activity and generated a minimal derivative, HQP09_9, which maintains the specific polyQ-binding activity. We demonstrated that HQP09 and HQP09_9 inhibited aggregation of Htt-N-53Q in vitro and exerted Ca(2+)-stabilizing and neuroprotective effects in experiments with primary striatal neuronal cultures derived from HD mice. We further demonstrated that intracerebroventricular delivery of HQP09 to an HD mouse model resulted in reduced accumulation of mutant Huntingtin aggregates and improved motor behavioral outcomes. These results suggest that HQP09 and similar peptoids hold promise as novel therapeutics for developing treatments for HD, SCA3, and other polyglutamine expansion disorders.

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Available from: Charlene Supnet, Oct 03, 2015
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    • "NMDAR inhibition leads to neutoprotective effect 2-APB, Enoxaparin (Lovenox) [44] [45] Calpain activation leads to change of NMDAR localization and apoptosis Calpain inhibitor calpeptin [46] Inhibition of store-operated calcium (SOC) pathway leads to neuroprotection Quinazoline [47] Inhibition of mitochondrial membrane permeability and cytoprotection Inhibitors of cytochrome c release [50] SIRT3 expression synthesis (À)-e-vineferin [51] GSK3 inhibition leads to neuron survival in HD model SB21676 [53] Oligomers Inhibition of Htt oligomerization Intrabody scFv-C4 [127] Inhibition of Htt oligomerization QBP1 peptide [133] Inhibition of Htt oligomerization Peptinoid HQP09 [134] Inhibition of mHtt cleavage Calpain inhibitors Caspase inhibitors [137] Aggregates Inhibition of tTG activity cystamine [68] GAPDH binding GAGDH binders Pefablock, Deprinil [77] Inducing molecular chaperones NG-094 [138] are capable of producing short chains of polyQ proteins, and these polypeptides, especially those localized to the nuclei, are especially dangerous because of their ability to exacerbate the effects described in Section 2. The data discussed above also show that caspase or calpain inhibitors may be effective factors in the therapy of polyQ-associated pathologies, especially at their early stages (Fig. 1). Oligomerization of polyQ tracts excised from the mutant proteins appears to be a prerequisite for their accumulation into large aggregates. "
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    ABSTRACT: Polyglutamine diseases are a group of pathologies affecting different parts of the brain and causing dysfunction and atrophy of certain neural cell populations. These diseases stem from mutations in various cellular genes that result in the synthesis of proteins with extended polyglutamine tracts. In particular, this concerns huntingtin, ataxins, and androgen receptor. These mutant proteins can form oligomers, aggregates, and, finally, aggresomes with distinct functions and different degrees of cytotoxicity. In this review, we analyze the effects of different forms of polyQ proteins on other proteins and their functions, which are considered as targets for therapeutic intervention.
    FEBS letters 05/2013; 587(13). DOI:10.1016/j.febslet.2013.05.022 · 3.17 Impact Factor
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    • "Nuclei were counterstained with cresyl violet. Consistent with previous findings [34], PBS-fed YAC128 mice showed significant Httexp aggregation in striatal cells, indicated by dark and condense staining in the nucleus, as compared to PBS-fed WT (Figure 6). Interestingly, dantrolene-fed YAC128 mice showed a weaker and distributed staining, which suggests that dantrolene dramatically reduced the degree of Httexp aggregation in striatal cells as compared to PBS-fed YAC128. "
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    ABSTRACT: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca2+ signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.
    Molecular Neurodegeneration 11/2011; 6(1):81. DOI:10.1186/1750-1326-6-81 · 6.56 Impact Factor
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    ABSTRACT: Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement. We correctly predicted the structure of a N-aryl peptoid trimer to within 0.2 Å rmsd-backbone and a cyclic peptoid nonamer to an accuracy of 1.0 Å rmsd-backbone. X-ray crystallographic structures are presented for a linear N-alkyl peptoid trimer and for the cyclic peptoid nonamer. The peptoid macrocycle structure features a combination of cis and trans backbone amides, significant nonplanarity of the amide bonds, and a unique “basket” arrangement of (S)-N(1-phenylethyl) side chains encompassing a bound ethanol molecule. REMD simulations of the peptoid trimers reveal that well folded peptoids can exhibit funnel-like conformational free energy landscapes similar to those for ordered polypeptides. These results indicate that physical modeling can successfully perform de novo structure prediction for small peptoid molecules.
    Proceedings of the National Academy of Sciences 09/2012; 109(36):14320-14325. DOI:10.1073/pnas.1209945109 · 9.67 Impact Factor
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