title: Expanded polyglutamine-binding peptoid as a novel therapeutic agent for treatment of Huntington's disease.
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.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xia
authors.initials: X
authors.lastname: Liang
authors.forename: Charlene
authors.initials: C
authors.lastname: Supnet
authors.forename: Mee Whi
authors.initials: MW
authors.lastname: Kim
authors.forename: Gregor P
authors.initials: GP
authors.lastname: Lotz
authors.forename: Guocheng
authors.initials: G
authors.lastname: Yang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy*; D017827:Machado-Joseph Disease / Q000188:drug therapy; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D034444:Peptoids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D034444:Peptoids; C097188:polyglutamine