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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    • "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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