期刊
ACS CHEMICAL NEUROSCIENCE
卷 10, 期 2, 页码 991-995出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00280
关键词
Amyloid-beta; cooperativity; benzothiazole; aggregation; alpha-svnuclein
资金
- National Institute On Aging of the National Institutes of Health [R01AG053577]
Amyloids are self-assembled protein aggregates that represent a major hallmark of many neurologic and systemic diseases. Among the common features of amyloids is the presence of a high density of multiple binding sites for small molecule ligands, making them an attractive target for design of multimeric binding agents. Here, we demonstrate that noncovalent, intermolecular interactions between a 1:1 mixture of oppositely charged benzothiazole molecules enhances their binding to two different amyloid aggregates: Alzheimer's-related amyloid-beta (A beta) peptides or Parkinson's-related alpha-synuclein (alpha S) proteins. We show that this mixture leads to positively cooperative binding to amyloid targets, with up to 10-fold enhancement of binding compared to the uncharged parent compound. The observed enhancement of amyloid binding using noncovalent interactions was similar in magnitude to a benzothiazole dimer to aggregated A beta. These results represent a novel strategy for designing amyloid-targeting molecules with enhanced affinity, which could aid in the development of new diagnostic or treatment strategies for amyloid-associated diseases.
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