Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors
of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition
of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation
in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have
found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified
associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a
focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for
maximizing on-target efficacy while minimizing off-target side effects.
Keywords: Alzheimer’s disease, aggregation, neurofibrillary tangle, paired helical filaments, tau.
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