Chaperone-like N-methyl peptide inhibitors of polyglutamine aggregation.

Polyglutamine expansion in the exon 1 domain of huntingtin leads to aggregation into beta-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, 5QMe(2) [Anth-K-Q-Q(Me(2))-Q-Q(Me(2))-Q-CONH(2), where Anth is N-methylanthranilic acid and Q(Me(2)) is side chain N-methyl Q], has only side chain methylations at alternate residues, highlighting the importance of side chain interactions in polyglutamine fibrillogenesis.

Mechanism of cis-inhibition of polyQ fibrillation by polyP: PPII oligomers and the hydrophobic effect.

PolyQ peptides teeter between polyproline II (PPII) and beta-sheet conformations. In tandem polyQ-polyP peptides, the polyP segment tips the balance toward PPII, increasing the threshold number of Gln residues needed for fibrillation. To investigate the mechanism of cis-inhibition by flanking polyP segments on polyQ fibrillation, we examined short polyQ, polyP, and tandem polyQ-polyP peptides.

Synthetic studies of complex immunostimulants from Quillaja saponaria: synthesis of the potent clinical immunoadjuvant QS-21Aapi.

QS-21 is one of the most promising new adjuvants for immune response potentiation and dose-sparing in vaccine therapy given its exceedingly high level of potency and its favorable toxicity profile. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV-1, and malaria are among the numerous maladies targeted in more than 80 recent and ongoing vaccine therapy clinical trials involving QS-21 as a critical adjuvant component for immune response augmentation. QS-21 is a natural product immunostimulatory adjuvant, eliciting both T-cell- and antibody-mediated immune responses with microgram doses.