Polymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of Aβ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Aβ42-induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Aβ toxicity and fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show that differential effects of the mono- and biflavonoids in Aβ fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting Aβ fibrillogenesis, accumulate nontoxic Aβ oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Aβ oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two Aβ binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Aβ toxicity.

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To develop a useful method for designing cell-selective antimicrobial peptides and to investigate the effect of incorporating peptoid residues into an alpha-helical model peptide on structure, function, and mode of action, we synthesized a series of model peptides incorporating Nala (Ala-peptoid) into different positions of an amphipathic alpha-helical model peptide (KLW). Incorporation of one or two Nala residues into the hydrophobic helix face of KLW was more effective at disrupting the alpha-helical structure and bacterial cell selectivity than incorporation into the hydrophilic helix face or hydrophobic/hydrophilic interface. Tryptophan fluorescence studies of peptide interaction with model membranes indicated that the cell selectivity of KLW-L9-a and KLW-L9,13-a is closely correlated with their selective interactions with negatively charged phospholipids. KLW-L9,13-a, which has two Nala residues in its hydrophobic helix face, showed a random structure in membrane-mimicking conditions. KLW-L9,13-a exhibited the highest selectivity toward bacterial cells, showing no hemolytic activity and no or less cytotoxicity compared with other peptides against four mammalian cell lines. Unlike other model peptides, KLW-L9,13-a caused no or little membrane depolarization in Staphylococcus aureus or lipid flip-flop in negatively charged vesicles. In addition, KLW-L9,13-a caused very little fluorescent dye leakage from negatively charged vesicles. Furthermore, confocal laser-scanning microscopy and DNA-binding assays showed that KLW-L9,13-a probably exerts its antibacterial action by penetrating the bacterial membrane and binding to cytoplasmic compounds (e.g., DNA), resulting in cell death. Collectively, our results demonstrate that the incorporation of two Nala residues into the central position of the hydrophobic helix face of noncell-selective alpha-helical peptides is a promising strategy for the rational design of intracellular, cell-selective antimicrobial peptides.

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A new triterpenoid, named alisol Q 23-acetate, as well as fourteen known terpenes, alisol B 23-acetate (2), alisol B (3), alismol (4), 10-O-methyl-alismoxide (5), alismoxide (6), 11-deoxyalisol C (7), 13β,17β-epoxyalisol B 23-acetate (8), 4β,12-dihydroxyguaian-6,10-diene (9), alisol C 23-acetate (10), alisolide (11), 16β-methoxyalisol B monoacetate (12), alisol A (13), 16β-hydroxyalisol B 23-acetate (14), alisol A 24-acetate (15) were isolated from the rhizomes of Alisma orientale. The structures of compounds (1-15) were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Among these isolates, antibacterial effect of compounds 2, 3, 10, and 15, major constituents of A. orientale was examined. The MIC values of compounds 2, 10, and 15 were 5-10 βg/mL against eight antibiotic resistant strains, which were lower than those from the positive controls (MICs of chloramphenicol and ampicillin were 5-80 μg/mL). Therefore, compounds 2, 10 and 15 exhibited the potent antibacterial activity.

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