AgHalo: A Facile Fluorogenic Sensor to Detect Drug‐Induced Proteome Stress

作者：Yu Liu, Matthew Fares, Noah P. Dunham, Zi Gao, Kun Miao, Xueyuan Jiang, Samuel S. Bollinger, Amie K. Boal, Xin Zhang · 发表于：Angewandte Chemie International Edition · 年份：2017 · DOI：10.1002/anie.201702417 · 被引用次数：116 · 研究领域：Ubiquitin and proteasome pathways、Protein Degradation and Inhibitors、Click Chemistry and Applications

Drug-induced proteome stress that involves protein aggregation may cause adverse effects and undermine the safety profile of a drug. Safety of drugs is regularly evaluated using cytotoxicity assays that measure cell death. However, these assays provide limited insights into the presence of proteome stress in live cells. A fluorogenic protein sensor is reported to detect drug-induced proteome stress prior to cell death. An aggregation prone Halo-tag mutant (AgHalo) was evolved to sense proteome stress through its aggregation. Detection of such conformational changes was enabled by a fluorogenic ligand that fluoresces upon AgHalo forming soluble aggregates. Using 5 common anticancer drugs, we exemplified detection of differential proteome stress before any cell death was observed. Thus, this sensor can be used to evaluate drug safety in a regime that the current cytotoxicity assays cannot cover and be generally applied to detect proteome stress induced by other toxins.