title: Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by "molecular tweezers" - from the test tube to animal models.
abstract: Despite decades of research, therapy for diseases caused by abnormal protein folding and aggregation (amyloidoses) is limited to treatment of symptoms and provides only temporary and moderate relief to sufferers. The failure in developing successful disease-modifying drugs for amyloidoses stems from the nature of the targets for such drugs - primarily oligomers of amyloidogenic proteins, which are distinct from traditional targets, such as enzymes or receptors. The oligomers are metastable, do not have well-defined structures, and exist in dynamically changing mixtures. Therefore, inhibiting the formation and toxicity of these oligomers likely will require out-of-the-box thinking and novel strategies. We review here the development of a strategy based on targeting the combination of hydrophobic and electrostatic interactions that are key to the assembly and toxicity of amyloidogenic proteins using lysine (K)-specific "molecular tweezers" (MTs). Our discussion includes a survey of the literature demonstrating the important role of K residues in the assembly and toxicity of amyloidogenic proteins and the development of a lead MT derivative called CLR01, from an inhibitor of protein aggregation in vitro to a drug candidate showing effective amelioration of disease symptoms in animal models of Alzheimer's and Parkinson's diseases.
authors.forename: Aida
authors.initials: A
authors.lastname: Attar
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building 1, Room 451, 635 Charles E. Young Drive South, Los Angeles, CA 90095-7334, USA. gbitan@mednet.ucla.edu.
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D000595:Amino Acid Sequence; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D023421:Models, Animal; D008969:Molecular Sequence Data; D010755:Organophosphates / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D055503:Protein Multimerization; D055672:Static Electricity; D013569:Synapses / Q000187:drug effects; D051844:alpha-Synuclein / Q000633:toxicity
chemical_list: D058227:Amyloidogenic Proteins; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D010755:Organophosphates; D051844:alpha-Synuclein