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.

• MeSH
• alfa-synuklein antagonisté a inhibitory   genetika   metabolismus   MeSH
• amyloid antagonisté a inhibitory   chemie   metabolismus   MeSH
• cirkulární dichroismus MeSH
• disulfidy chemie   MeSH
• látky ovlivňující centrální nervový systém chemie   farmakologie   MeSH
• lidé MeSH
• multimerizace proteinu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH