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Issue 76, 2016
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Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

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Abstract

Molecular tweezers represent the first class of artificial receptor molecules that have made the way from a supramolecular host to a drug candidate with promising results in animal tests. Due to their unique structure, only lysine and arginine are well complexed with exquisite selectivity by a threading mechanism, which unites electrostatic, hydrophobic and dispersive attraction. However, tweezer design must avoid self-dimerization, self-inclusion and external guest binding. Moderate affinities of molecular tweezers towards sterically well accessible basic amino acids with fast on and off rates protect normal proteins from potential interference with their biological function. However, the early stages of abnormal Aβ, α-synuclein, and TTR assembly are redirected upon tweezer binding towards the generation of amorphous non-toxic materials that can be degraded by the intracellular and extracellular clearance mechanisms. Thus, specific host–guest chemistry between aggregation-prone proteins and lysine/arginine binders rescues cell viability and restores animal health in models of AD, PD, and TTR amyloidosis.

Graphical abstract: Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

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Publication details

The article was received on 02 Jun 2016, accepted on 27 Jul 2016 and first published on 29 Jul 2016


Article type: Feature Article
DOI: 10.1039/C6CC04640A
Citation: Chem. Commun., 2016,52, 11318-11334
  • Open access: Creative Commons BY-NC license
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    Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

    T. Schrader, G. Bitan and F. Klärner, Chem. Commun., 2016, 52, 11318
    DOI: 10.1039/C6CC04640A

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