ArticleNature chemical biology2020
Discovery of small-molecule enzyme activators by activity-based protein profiling.
Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 49 citations in OpenAlex.
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- Development of a human genetics-guided priority score for 19,365 genes and 399 drug indications.Nature genetics · 2024Article
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
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- Activity-based protein profiling - finding general solutions to specific problems.Israel journal of chemistry · 2023Article
- Heliangin acts as a covalent ligand of RPS2 that disrupts pre-rRNA metabolic processes inActa pharmaceutica Sinica. B · 2023Article
- Identification of fungal lignocellulose-degrading biocatalysts secreted by Phanerochaete chrysosporium via activity-based protein profiling.Communications biology · 2022Article
- Unraveling the mystery of efficacy in Chinese medicine formula: New approaches and technologies for research on pharmacodynamic substances.Arabian journal of chemistry · 2022Review
- Identification of sitagliptin binding proteins by affinity purification mass spectrometry.Acta biochimica et biophysica Sinica · 2022Article
- Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition.Metabolites · 2021Review
- Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.ACS medicinal chemistry letters · 2021Article
- Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets.ACS central science · 2021Article
- Development and biological applications of sulfur-triazole exchange (SuTEx) chemistry.RSC chemical biology · 2021Article
- Proteomic Approaches to Study SARS-CoV-2 Biology and COVID-19 Pathology.Journal of proteome research · 2021Article
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Authors and funding
20 authors at 1 institution in 1 country.
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Abstract
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.
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