Discovery of small-molecule enzyme activators by activity-based protein profiling.

Autor: Kok BP; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Ghimire S; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Kim W; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Chatterjee S; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Johns T; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Kitamura S; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Eberhardt J; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Ogasawara D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Xu J; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Sukiasyan A; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Kim SM; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Godio C; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Bittencourt JM; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Cameron M; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Galmozzi A; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Forli S; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Wolan DW; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Cravatt BF; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Boger DL; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. boger@scripps.edu., Saez E; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. esaez@scripps.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Sep; Vol. 16 (9), pp. 997-1005. Date of Electronic Publication: 2020 Jun 08.
DOI: 10.1038/s41589-020-0555-4
Abstrakt: Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.
Databáze: MEDLINE
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