期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 42, 页码 16958-16969出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja206279b
关键词
-
资金
- UCLA's Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development
- American Health Assistance Foundation [A2008-350]
- NIH [RR20004]
- NIH/NCRR [S10 RR023045]
- NIH/NIA [AG027818]
- Deutsche Forschungsgemeinschaft [EH100/14-1]
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 beta-protein (A beta) to further explore the binding site(s) of CLAW 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 A beta at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology from A beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据