Sinha, Sharmistha; Lopes, Dahabada H. J.; Du, Zhenming; Pang, Eric S.; Shanmugam, Akila; Lomakin, Aleksey; Talbiersky, Peter; Tennstaedt, Annette; McDaniel, Kirsten; Bakshi, Reena; Kuo, Pei-Yi; Ehrmann, Michael; Benedek, George B.; Loo, Joseph A.; Klärner, Frank-Gerrit; Schrader, Thomas; Wang, Chunyu; Bitan, Gal:
Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins
2011
In: Journal of the American Chemical Society : JACS, Jg. 133 (2011), Heft 42, S. 16958 - 16969.
Artikel/Aufsatz in Zeitschrift2011Biologie
Titel:
Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins
Autor(in):
Sinha, Sharmistha; Lopes, Dahabada H. J.; Du, Zhenming; Pang, Eric S.; Shanmugam, Akila; Lomakin, Aleksey; Talbiersky, Peter; Tennstaedt, Annette; McDaniel, Kirsten; Bakshi, Reena; Kuo, Pei-Yi; Ehrmann, MichaelLSF; Benedek, George B.; Loo, Joseph A.; Klärner, Frank-GerritLSF; Schrader, ThomasLSF; Wang, Chunyu; Bitan, Gal
Erscheinungsjahr
2011
WWW URL

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.