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Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. | LitMetric

AI Article Synopsis

  • Amyloidoses are diseases caused by abnormal protein folding and without a current cure, making the modulation of protein self-assembly a key focus for treatment.
  • Researchers discovered a compound called CLR01, which inhibits the aggregation of harmful proteins by targeting and disrupting specific interactions crucial for their assembly while showing no toxicity at effective concentrations.
  • CLR01 binds to lysine residues in amyloid β-protein (Aβ) early in the assembly process, creating nontoxic complexes that resemble Aβ oligomers but do not invoke an immune response, indicating its potential as a therapeutic strategy for amyloidoses.

Article Abstract

Amyloidoses are diseases characterized by abnormal protein folding and self-assembly, for which no cure is available. Inhibition or modulation of abnormal protein self-assembly, 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210512PMC
http://dx.doi.org/10.1021/ja206279bDOI Listing

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