Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by "molecular tweezers" - from the test tube to animal models.

摘要: Despite decades of research, therapy for diseases caused by abnormal protein folding and aggregation (amyloidoses) is limited to treatment symptoms provides only temporary moderate relief sufferers. The failure in developing successful disease-modifying drugs amyloidoses stems from the nature targets such - primarily oligomers amyloidogenic proteins, which are distinct traditional targets, as enzymes or receptors. metastable, do not have well-defined structures, exist dynamically changing mixtures. Therefore, inhibiting formation toxicity these likely will require out-of-the-box thinking novel strategies. We review here development a strategy based on targeting combination hydrophobic electrostatic interactions that key assembly proteins using lysine (K)-specific "molecular tweezers" (MTs). Our discussion includes survey literature demonstrating important role K residues lead MT derivative called CLR01, an inhibitor vitro drug candidate showing effective amelioration disease animal models Alzheimer's Parkinson's diseases.