A Peptide Hairpin Inhibitor of Amyloid β-Protein Oligomerization and Fibrillogenesis

Medical Scientist Training Program, David Geffen School of Medicineat UCLA, USA.
Biochemistry (Impact Factor: 3.02). 10/2009; 48(48):11329-31. DOI: 10.1021/bi901325g
Source: PubMed


Amyloid beta-protein (Abeta) self-assembly is linked strongly to Alzheimer's disease. We found that PP-Leu, a tridecapeptide analogue of broad-spectrum antiviral peptides termed theta-defensins, potently inhibits Abeta oligomer and fibril formation. This effect appeared to be mediated through sequestration of the amyloidogenic Abeta peptide in colloid-like assemblies. PP-Leu comprises a turn formed by a d-Pro-l-Pro amino acid dyad and stabilized by a disulfide bond, a motif that was exceptionally resistant to endoproteinase K digestion. This combination of assembly inhibitory activity and protease resistance suggests that PP-Leu may have potential therapeutic value.

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Available from: Piotr Ruchala, Apr 09, 2015
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    • "(C) ThT monitoring of 10 μM Aβ aggregation and inhibitory effects of 100 μM peptides present from the beginning of the aggregation at 37°C. Inhibition values were taken at 12 hr due the decay in ThT fluorescence, particularly for uninhibited samples, which has been described elsewhere (Yamin et al., 2009). (D) Aβ toxicity after 6 hr of aggregation, as probed using the MTT assay and the SH-SY5Y cell line. "
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    ABSTRACT: Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called α-sheet. Here we report the experimental characterization of peptides designed to be complementary to the α-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, β-amyloid peptide (Aβ) and transthyretin, by these designed α-sheet peptides. When immobilized the α-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting α-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics. DOI:
    eLife Sciences 07/2014; 3(3):e01681. DOI:10.7554/eLife.01681 · 9.32 Impact Factor
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    • "Higher order oligomers ( pentameric/hexameric assemblies) have been studied by MD and show different effects between the central hydrophobic and carboxy-terminal regions when Ab 40 and Ab 42 are compared (Urbanc et al. 2010). Synthetic oligomers are also being used in attempts to discover small molecules which are able to target these specific assemblies (Davis and Berkowitz 2009a; Davis et al. 2009; Feng et al. 2009; Liu et al. 2009a; Nerelius et al. 2009; Pitt et al. 2009; Riviere et al. 2009; Smith et al. 2009; Sun et al. 2009; Yamin et al. 2009; Hawkes et al. 2010; Ladiwala et al. 2010). "
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    ABSTRACT: Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochemistry and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochemistry, and current attempts to understand how a range of Aβ assemblies, including soluble oligomers and insoluble fibrils, may precipitate and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key molecular factor in the etiology of Alzheimer disease remains controversial, clinical trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy.
    Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a006262. DOI:10.1101/cshperspect.a006262 · 9.47 Impact Factor
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    • "homoserine O-methyl ether, Mes methanesulfonyl group, Nle norleucine, Nva norvaline, Ser Me serine O-methyl ether, Thr Me threonine O-methyl ether, Tle tert-Leucine, PEG 5 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoic acid synthesis, (3) overall low cost of production, and (4) previously reported significant resistance to enzymatic degradation (Yamin et al. 2009). As an outcome, a new library of second generation DpVs (DpVs 2G , analogues DpV1601- 1632) was created. "
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    ABSTRACT: Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).
    International Journal of Peptide Research and Therapeutics 12/2011; 17(4):325-336. DOI:10.1007/s10989-011-9272-x · 0.91 Impact Factor
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