Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 30, Pages 8672-8676Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201702417
Keywords
biosensors; cytotoxicity; fluorescent probes; protein aggregation; proteome stress
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Funding
- Burroughs Wellcome Fund Career Award at the Scientific Interface
- Paul Berg Early Career Professorship
- Lloyd and Dottie Huck Early Career Award
- NIH [GM100011]
- Searle Scholars Program
- DOE Office of Science [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
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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.
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