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 diseasemodifying 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.
Keywords: Amyloid, Alzheimer's disease, Parkinson's disease, inhibitor, oligomer, lysine, molecular tweezers.
Current Pharmaceutical Design
Title:Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by “ Molecular Tweezers” - from the Test Tube to Animal Models
Volume: 20 Issue: 15
Author(s): Aida Attar and Gal Bitan
Affiliation:
Keywords: Amyloid, Alzheimer's disease, Parkinson's disease, inhibitor, oligomer, lysine, molecular tweezers.
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 diseasemodifying 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.
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Cite this article as:
Attar Aida and Bitan Gal, Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by “ Molecular Tweezers” - from the Test Tube to Animal Models, Current Pharmaceutical Design 2014; 20 (15) . https://dx.doi.org/10.2174/13816128113199990496
DOI https://dx.doi.org/10.2174/13816128113199990496 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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