Taup rotein aggregates are ar ecognized neuropathological feature in Alzheimersd isease as well as many other neurodegenerative disorders,knownastauopathies.The development of tau-targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear.Here,weperformed acell-based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified as mall molecule,S B1617, capable of suppressing abnormal tau protein aggregation. By applying label-free target identification technology,w er evealed that the transient enhancement of protein kinase-like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress-responsive SB1617 targets,P DIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies.The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and am ouse model with traumatic brain injury,atauopathy knowntoinvolve ER stress.
Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections and small-molecule libraries for high-throughput screening (HTS) and high-content screening (HCS) has emerged as a powerful tool in the development of novel therapeutic agents. Herein, we review the recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries.
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