Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins
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Author(s)
Sinha, Sharmistha
Lopes, Dahabada H. J.
Du, Zhenming
Pang, Eric S.
Shanmugam, Akila
Lomakin, Aleksey
Talbiersky, Peter
Tennstaedt, Annette
McDaniel, Kirsten
Bakshi, Reena
Date Issued
September 2011
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Sinha, Sharmistha et al. “Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins.” Journal of the American Chemical Society 133.42 (2011): 16958–16969.
Version
Author's final manuscript
Abstract
Amyloidoses are diseases characterized by abnormal
protein folding and self-assembly, for which no cure is
available. Inhibition or modulation of abnormal protein selfassembly,
therefore, is an attractive strategy for prevention and
treatment of amyloidoses. We examined Lys-specific molecular
tweezers and discovered a lead compound termed CLR01,
which is capable of inhibiting the aggregation and toxicity of
multiple amyloidogenic proteins by binding to Lys residues and
disrupting hydrophobic and electrostatic interactions important
for nucleation, oligomerization, and fibril elongation. Importantly,
CLR01 shows no toxicity at concentrations substantially
higher than those needed for inhibition. We used amyloid β-
protein (Aβ) to further explore the binding site(s) of CLR01
and the impact of its binding on the assembly process. Mass spectrometry and solution-state NMR demonstrated binding of CLR01
to the Lys residues in Aβ at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology
from Aβ oligomers but were nontoxic and were not recognized by the oligomer-specific antibody A11. Thus, CLR01 binds already at
the monomer stage and modulates the assembly reaction into formation of nontoxic structures. The data suggest that molecular
tweezers are unique, process-specific inhibitors of aberrant protein aggregation and toxicity, which hold promise for developing
disease-modifying therapy for amyloidoses.
Description
Author Manuscript 2012 October 26.
MIT Department
MIT Materials Research Laboratory
Massachusetts Institute of Technology. Department of Physics
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DOI of Published Version
https://doi.org/10.1021/ja206279b
