Discovery of small-molecule enzyme activators by activity-based protein profiling
| Autor: | Dale L. Boger, Daisuke Ogasawara, Julia M. Bittencourt, Enrique Saez, Shreyosree Chatterjee, C. Godio, Ara Sukiasyan, Andrea Galmozzi, Jerome Eberhardt, Benjamin F. Cravatt, Michael D. Cameron, Stefano Forli, Woojoo Kim, Tyler Johns, Dennis W. Wolan, Seiya Kitamura, Bernard P. Kok, Sean M. Kim, Janice H Xu, Srijana Ghimire |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Enzyme Activators Mice Obese Fluorescence Polarization Molecular Dynamics Simulation Article Small Molecule Libraries 03 medical and health sciences Enzyme activator Structure-Activity Relationship Catalytic triad Drug Discovery Animals Humans Molecular Biology 030304 developmental biology chemistry.chemical_classification Metabolic Syndrome 0303 health sciences Molecular Structure Activator (genetics) Drug discovery 030302 biochemistry & molecular biology Activity-based proteomics Serine hydrolase Cell Biology Small molecule High-Throughput Screening Assays Mice Inbred C57BL Enzyme HEK293 Cells Biochemistry chemistry Insulin Resistance Lysophospholipase |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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: | OpenAIRE |
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