Amyloid β-protein assembly: The effect of molecular tweezers CLR01 and CLR03

The Journal of Physical Chemistry. B
Xueyun ZhengMichael T Bowers

Abstract

The early oligomerization of amyloid β-protein (Aβ) has been shown to be an important event in the pathology of Alzheimer's disease (AD). Designing small molecule inhibitors targeting Aβ oligomerization is one attractive and promising strategy for AD treatment. Here we used ion mobility spectrometry coupled to mass spectrometry (IMS-MS) to study the different effects of the molecular tweezers CLR01 and CLR03 on Aβ self-assembly. CLR01 was found to bind to Aβ directly and disrupt its early oligomerization. Moreover, CLR01 remodeled the early oligomerization of Aβ42 by compacting the structures of dimers and tetramers and as a consequence eliminated higher-order oligomers. Unexpectedly, the negative-control derivative, CLR03, which lacks the hydrophobic arms of the tweezer structure, was found to facilitate early Aβ oligomerization. Our study provides an example of IMS as a powerful tool to study and better understand the interaction between small molecule modulators and Aβ oligomerization, which is not attainable by other methods, and provides important insights into therapeutic development of molecular tweezers for AD treatment.

References

Feb 6, 1996·Proceedings of the National Academy of Sciences of the United States of America·A LomakinD B Teplow
Mar 16, 2001·Trends in Neurosciences·W L KleinC E Finch
Mar 29, 2001·Physiological Reviews·D J Selkoe
Dec 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Gal BitanDavid B Teplow
Aug 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yuesong GongWilliam L Klein
Aug 6, 2004·Nature·Mark P Mattson
Dec 14, 2004·The Journal of Biological Chemistry·Fusheng YangGregory M Cole
Feb 17, 2005·Journal of the American Chemical Society·Summer L BernsteinMichael T Bowers
Oct 13, 2005·Journal of the American Chemical Society·Michael FokkensFrank-Gerrit Klärner
Feb 28, 2006·Protein Science : a Publication of the Protein Society·Andrij BaumketnerJoan-Emma Shea
Mar 17, 2006·Nature·Sylvain LesnéKaren H Ashe
Mar 18, 2006·Drugs in R&D·Donna M BartenCharles F Albright
Sep 20, 2006·Accounts of Chemical Research·David B TeplowH Eugene Stanley
Feb 9, 2007·Journal of Neurochemistry·Dominic M Walsh, Dennis J Selkoe
Oct 24, 2007·ChemMedChem·Cliff I StainsIndraneel Ghosh
May 31, 2008·Nature Structural & Molecular Biology·Dagmar E EhrnhoeferErich E Wanker
Sep 10, 2008·Proceedings of the National Academy of Sciences of the United States of America·Erica A FradingerGal Bitan
Mar 31, 2009·Angewandte Chemie·Roland Jakob-Roetne, Helmut Jacobsen
Apr 11, 2009·Annals of Neurology·Randall J BatemanDavid M Holtzman
Apr 23, 2011·Current Topics in Medicinal Chemistry·Bruno P Imbimbo, Giuseppe A M Giardina
Sep 16, 2011·Journal of the American Chemical Society·Sharmistha SinhaGal Bitan
Dec 2, 2011·Biochemistry·Megan Murray GesselMichael T Bowers
Jan 19, 2012·The Journal of Biological Chemistry·Xueyun ZhengMichael T Bowers
Mar 1, 2012·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Shubhangi PrabhudesaiJeff M Bronstein
Jun 26, 2012·Accounts of Chemical Research·Frank-Gerrit Klärner, Thomas Schrader
Nov 23, 2012·ACS Chemical Neuroscience·Megan Murray GesselMichael T Bowers
Nov 28, 2012·Brain : a Journal of Neurology·Aida AttarGal Bitan
Jun 12, 2013·The Journal of Organic Chemistry·Som DuttThomas Schrader
Apr 3, 2014·Chemical Society Reviews·Arun K Ghosh, Heather L Osswald
May 21, 2014·Angewandte Chemie·Hong Hee LeeHugh I Kim

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Citations

Oct 1, 2015·ACS Chemical Neuroscience·Robin RoychaudhuriDavid B Teplow
Dec 3, 2015·ACS Chemical Neuroscience·Natália E C de AlmeidaMichael T Bowers
Apr 14, 2017·Journal of the American Chemical Society·Tobias VöpelElsa Sanchez-Garcia
Feb 22, 2018·Journal of the American Society for Mass Spectrometry·Jasmine S-H WangKen K-C Yeung
Jun 7, 2018·Chemical Communications : Chem Comm·Annika RöckerJan Münch
Aug 1, 2018·Journal of the American Society for Mass Spectrometry·Michael NshanianJoseph A Loo
Jul 21, 2015·FEBS Letters·Leonid Breydo, Vladimir N Uversky
Sep 2, 2017·Journal of the American Heart Association·Na XuJeffrey Robbins
Oct 1, 2020·Journal of Molecular Modeling·Ali Abdullah Issa, Hasan R Obayes
Apr 30, 2017·Chemical Science·Xu HanRoger M Leblanc
Oct 31, 2019·Physical Chemistry Chemical Physics : PCCP·Andrew G T Pyo, Michael T Woodside
Oct 22, 2019·Frontiers in Chemistry·Inesa HadrovicThomas Schrader
Oct 14, 2019·Journal of Pharmaceutical and Biomedical Analysis·Angela De SimoneVincenza Andrisano
Oct 24, 2020·Beilstein Journal of Organic Chemistry·Peter BayerChristine Beuck
Feb 20, 2021·International Journal of Biological Macromolecules·Mueed Ur RahmanHai-Feng Chen
Mar 27, 2021·International Journal of Biological Macromolecules·Cameron WellsLezanne Ooi
Apr 15, 2021·Cell Chemical Biology·Ravit MalishevRaz Jelinek
May 2, 2018·Journal of the American Society for Mass Spectrometry·Matthew A DowneyMichael T Bowers
Apr 7, 2015·ACS Chemical Biology·Dahabada H J LopesGal Bitan
Aug 2, 2017·ACS Chemical Neuroscience·Witold Gospodarczyk, Maciej Kozak
Jun 3, 2017·ACS Central Science·Massimiliano PorriniValérie Gabelica
Apr 10, 2018·The Journal of Physical Chemistry. B·Sumit MittalElsa Sanchez-Garcia
Sep 15, 2020·Journal of the American Chemical Society·Tatjana WeilJan Münch
Aug 28, 2021·Chemical Reviews·Jack L BennettWilliam A Donald
Dec 14, 2019·ACS Chemical Neuroscience·Albert W PilkingtonJustin Legleiter

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Methods Mentioned

BETA
electron microscopy
NMR

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