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7‑Methoxytacrine and 2‑Aminobenzothiazole Heterodimers: Structure–Mechanism Relationship of Amyloid Inhibitors Based on Rational Design
journal contribution
posted on 2020-02-21, 15:39 authored by Miroslav Gancar, Kiet Ho, Sk. Abdul Mohid, Nguyen Quoc Thai, Zuzana Bednarikova, H. Linh Nguyen, Anirban Bhunia, Eugenie Nepovimova, Mai Suan Li, Zuzana GazovaThe 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.