Structure and mechanism of action of tau aggregation inhibitors.
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.
Katryna
K
Cisek
Grace L
GL
Cooper
Carol J
CJ
Huseby
1060 Carmack Rd, Columbus, OH 43210, USA. kuret.3@osu.edu.
Jeff
J
Kuret
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D014150:Antipsychotic Agents; D016875:tau Proteins