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Design of Optical‐Imaging Probes by Screening of Diverse Substrate Libraries Directly in Disease‐Tissue Extracts
Author(s) -
Tholen Martina,
Yim Joshua J.,
Groborz Katarzyna,
Yoo Euna,
Martin Brock A.,
Berg Nynke S.,
Drag Marcin,
Bogyo Matthew
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202006719
Subject(s) - computational biology , substrate (aquarium) , in vivo , molecular probe , enzyme , substrate specificity , chemistry , peptide library , peptide , combinatorial chemistry , nanotechnology , biochemistry , computer science , biology , materials science , peptide sequence , microbiology and biotechnology , ecology , gene , dna
Abstract 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.