期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 43, 页码 19143-19152出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202006719
关键词
disease tissue; in-vivo imaging; probe design; protease profiling
资金
- NIH [R01 EB026285]
- Stanford Cancer Institute Translational Oncology Program seed grant
- DFG Research Fellowship [TH2139/1-1]
- Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
- NSF Graduate Research Fellowship [DGE-114747]
- European Union under the European Regional Development Fund
- National Science Centre in Poland
- [TEAM/2017-4/32]
Fluorescently quenched probes that are specifically activated in the cancer microenvironment have great potential application for diagnosis, early detection, and surgical guidance. These probes are often designed to target specific enzymes associated with diseases by direct optimization using single purified enzymes. However, this can result in painstaking chemistry efforts to produce a probe with suboptimal performance when applied in vivo. We describe here an alternate, unbiased activity-profiling approach in which whole tissue extracts are used to directly identify optimal peptide sequences for probe design. Screening of tumor extracts with a hybrid combinatorial substrate library (HyCoSuL) identified a combination of natural and non-natural amino-acid residues that was used to generate highly efficient tumor-specific probes. This new strategy simplifies and enhances the process of probe optimization without any a priori knowledge of enzyme targets and has the potential to be applied to diverse disease states using clinical or animal-model tissue samples.
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