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• W1988038897 abstract "Polyglutamine expansion in the exon 1 domain of huntingtin leads to aggregation into β-sheet-rich insoluble aggregates associated with Huntington’s disease. We assessed eight polyglutamine peptides with different permutations of N-methylation of backbone and side chain amides as potential inhibitors of polyglutamine aggregation. Surprisingly, the most effective inhibitor, 5QMe2 [Anth-K-Q-Q(Me2)-Q-Q(Me2)-Q-CONH2, where Anth is N-methylanthranilic acid and Q(Me2) is side chain N-methyl Q], has only side chain methylations at alternate residues, highlighting the importance of side chain interactions in polyglutamine fibrillogenesis. Above a 1:1 stoichiometric ratio, 5QMe2 can completely prevent fibrillation of a synthetic aggregating peptide, YAQ12A; it also shows significant inhibition at substoichiometric ratios. Surface plasmon resonance (SPR) measurements show a moderate Kd with very fast kon and koff values. Sedimentation equilibrium analytical ultracentrifugation indicates that 5QMe2 is predominantly or entirely monomeric at concentrations of ≤1 mM and that it forms a 1:1 stoichiometric complex with a fibril-forming target, YAQ12A. 5QMe2 inhibits not only nucleation of YAQ12A but also fibril extension, as shown by the fact that it also inhibits seeded fibril growth where the nucleation steps are bypassed. 5QMe2 acts on its targets only when they are in the PPII-like conformation, but not after they undergo a transition to β-sheets. Thus, 5QMe2 does not disassemble preformed YAQ12A; this contrasts with our previously described, backbone N-methylated inhibitors of β-amyloid aggregation [Gordon, D. J., et al. (2001) Biochemistry 40, 8237−8245; Gordon, D. J., et al. (2002) J. Pept. Res. 60, 37−55]. The mode of action of 5QMe2 is reminiscent of that of chaperones, because it binds and releases its targets very rapidly and maintains them in a nonaggregation-prone, monomeric state, in this case, the polyproline II (PPII)-like conformation, as shown by circular dichroism spectroscopy." @default.
• W1988038897 created "2016-06-24" @default.
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• W1988038897 date "2010-07-30" @default.
• W1988038897 modified "2023-09-27" @default.
• W1988038897 title "Chaperone-like <i>N</i>-Methyl Peptide Inhibitors of Polyglutamine Aggregation" @default.
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• W1988038897 doi "https://doi.org/10.1021/bi1006095" @default.
• W1988038897 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2965777" @default.
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