Expanded polyglutamine-binding peptoid as a novel therapeutic agent for treatment of Huntington's disease

Xuesong Chen, Jun Wu, Yuan Luo, Xia Liang, Charlene Supnet, Mee Whi Kim, Gregor P. Lotz, Guocheng Yang, Paul J. Muchowski, Thomas Kodadek, Ilya Bezprozvanny

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1113-1125
Number of pages13
JournalChemistry and Biology
Volume18
Issue number9
DOIs
StatePublished - Sep 23 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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