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Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to A? peptide.

ABSTRACT: Stereochemistry is vital for pharmaceutical development and can determine drug efficacy. Herein, 10 pairs of asymmetric triplex metallohelix enantiomers as a library were used to screen inhibitors of amyloid ? (A?) aggregation via a fluorescent cell-based high-throughput method. Intriguingly, ? enantiomers show a stronger inhibition effect than ? enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key role in the A? interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the ? enantiomer to A? is much faster than that of the ? enantiomer. Furthermore, studies in enzyme digestion, isothermal titration calorimetry, nuclear magnetic resonance, and computational docking demonstrate that the enantiomers bind to the central hydrophobic ?-helical region of A?13-23, although with different modes for the ? and ? enantiomers. Finally, an in vivo study showed that these metallohelices extend the life span of the Caenorhabditis elegans CL2006 strain by attenuating A?-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer's disease.

SUBMITTER: Guan Y

PROVIDER: S-EPMC5775025 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aβ peptide.

Guan Yijia Y Du Zhi Z Gao Nan N Cao Yue Y Wang Xiaohui X Scott Peter P Song Hualong H Ren Jinsong J Qu Xiaogang X

Science advances 20180119 1

Stereochemistry is vital for pharmaceutical development and can determine drug efficacy. Herein, 10 pairs of asymmetric triplex metallohelix enantiomers as a library were used to screen inhibitors of amyloid β (Aβ) aggregation via a fluorescent cell-based high-throughput method. Intriguingly, Λ enantiomers show a stronger inhibition effect than Δ enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key r ...[more]

PMID: 29372182

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Project description:BackgroundThe deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.ResultsTracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.ConclusionsThese results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.

Dataset Information

Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to A? peptide.

Publications

Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aβ peptide.

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