title: Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins.
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.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Sinha
authors.forename: Dahabada H J
authors.initials: DH
authors.lastname: Lopes
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Du
authors.forename: Eric S
authors.initials: ES
authors.lastname: Pang
authors.forename: Akila
authors.initials: A
authors.lastname: Shanmugam
authors.forename: Aleksey
authors.initials: A
authors.lastname: Lomakin
authors.forename: Peter
authors.initials: P
authors.lastname: Talbiersky
authors.forename: Annette
authors.initials: A
authors.lastname: Tennstaedt
authors.forename: Kirsten
authors.initials: K
authors.lastname: McDaniel
authors.forename: Reena
authors.initials: R
authors.lastname: Bakshi
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Kuo
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: George B
authors.initials: GB
authors.lastname: Benedek
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Loo
authors.forename: Frank-Gerrit
authors.initials: FG
authors.lastname: Klärner
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000686:Amyloidosis / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D008239:Lysine / Q000737:chemistry* / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D010755:Organophosphates; D011506:Proteins; D008239:Lysine