Issue 76, 2016

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

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

Article information

Article type
Feature Article
Submitted
02 Jun 2016
Accepted
27 Jul 2016
First published
29 Jul 2016
This article is Open Access
Creative Commons BY-NC license

Chem. Commun., 2016,52, 11318-11334

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

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements