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J Med Chem ; 62(22): 10342-10351, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31625739

ABSTRACT

Aggregation of the neuronal protein α-synuclein into amyloid fibrils plays a central role in the development of Parkinson's disease. Growth of fibrils can be suppressed by blocking fibril ends from their interaction with monomeric proteins. In this work, we constructed inhibitors that bind to the ends of α-synuclein amyloid fibrils with very high affinity. They are based on synthetic α-synuclein dimers and interact with fibrils via two monomeric subunits adopting conformation that efficiently blocks fibril elongation. By tuning the charge of dimers, we further enhanced the binding affinity and prepared a construct that inhibits fibril elongation at nanomolar concentration (IC50 ≈ 20 nM). To the best of our knowledge, it is the most efficient inhibitor of α-synuclein fibrillization.


Subject(s)
Amyloid/antagonists & inhibitors , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , alpha-Synuclein/antagonists & inhibitors , alpha-Synuclein/metabolism , Amyloid/chemistry , Amyloid/metabolism , Circular Dichroism , Disulfides/chemistry , Humans , Protein Multimerization , Structure-Activity Relationship , alpha-Synuclein/genetics
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