Chemoproteomics-Enabled De Novo Discovery of Photoswitchable Carboxylesterase Inhibitors for Optically Controlled Drug Metabolism.

Autor: Dwyer BG; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Wang C; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.; Current address: Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA., Abegg D; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Racioppo B; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Qiu N; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Zhao Z; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Pechalrieu D; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Shuster A; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA., Hoch DG; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.; Current address: Laboratory of Organic Chemistry, ETH Zürich, 8093, Zürich, Switzerland., Adibekian A; Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2021 Feb 08; Vol. 60 (6), pp. 3071-3079. Date of Electronic Publication: 2020 Dec 07.
DOI: 10.1002/anie.202011163
Abstrakt: Herein, we report arylazopyrazole ureas and sulfones as a novel class of photoswitchable serine hydrolase inhibitors and present a chemoproteomic platform for rapid discovery of optically controlled serine hydrolase targets in complex proteomes. Specifically, we identify highly potent and selective photoswitchable inhibitors of the drug-metabolizing enzymes carboxylesterases 1 and 2 and demonstrate their pharmacological application by optically controlling the metabolism of the immunosuppressant drug mycophenolate mofetil. Collectively, this proof-of-concept study provides a first example of photopharmacological tools to optically control drug metabolism by modulating the activity of a metabolizing enzyme. Our arylazopyrazole ureas and sulfones offer synthetically accessible scaffolds that can be expanded to identify specific photoswitchable inhibitors for other serine hydrolases, including lipases, peptidases, and proteases. Our chemoproteomic platform can be applied to other photoswitches and scaffolds to achieve optical control over diverse protein classes.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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