7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design
ACS Chemical Neuroscience, ISSN: 1948-7193, Vol: 11, Issue: 5, Page: 715-729
2020
- 12Citations
- 22Captures
- 1Mentions
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations12
- Citation Indexes12
- 12
- CrossRef8
- Captures22
- Readers22
- 22
- Mentions1
- News Mentions1
- 1
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7-MEOTA and 2-aminobenzothiazole heterodimers: structure-mechanism relationship of amyloid inhibitors based on rational design.
ACS Chem Neurosci. 2020 Feb 3; Authors: Gancar M, Ho K, Mohid SA, Thai NQ, Bednarikova Z, Nguyen HL, Bhunia A, Nepovimova E, Li MS, Gazova Z PubMed: 32011847 Submit Comment
Article Description
The formation and accumulation of amyloid aggregates are the phenomena that accompany amyloidoses, which are currently untreatable and include Alzheimer's and Parkinson's diseases, diabetes mellitus, non-neuropathic lysozyme systemic amyloidosis, and others. One of the very promising therapeutic approaches seems to be an inhibition of amyloid formation and/or clearance of amyloid aggregates. Small molecules have a great potential to interfere with amyloid fibrillation of peptides and polypeptides, which can be improved by connection of cyclic structures into single multicyclic molecules and their dimerization. In our study, we focused on heterodimers consisting of 7-methoxytacrine (7-MEOTA) and 2-aminobenzothiazole (BTZ) parent molecules connected by an aliphatic linker. Using in vitro and in silico methods, we investigated the ability of studied compounds to inhibit the amyloid aggregation of hen egg white lysozyme. Heterodimerization led to significant improvement of inhibitory activity compared to that of the parent molecules. The efficiency of the heterodimers varied; the most effective inhibitor contained the longest linker, eight carbons long. We suggest that binding of a heterodimer to a lysozyme blocks the interaction between the β-domain and C-helix region essential for the formation of amyloid cross-β structure. Elongation of the linker ultimately enhances the compound's ability to prevent this interaction by allowing the BTZ part of the heterodimer to bind more effectively, increasing the compound's binding affinity, and also by greater steric obstruction. This study represents an important contribution to the recent rational design of potential lead small molecules with anti-amyloid properties, and the heterodimers studied are prospective candidates for the treatment of systemic lysozyme amyloidosis and other amyloid-related diseases.
Bibliographic Details
American Chemical Society (ACS)
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