Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2 |
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| Authors: | Joseph MG Nagano Ku-Lung Hsu Landon R Whitby Micah J Niphakis Anna E Speers Steven J Brown Timothy Spicer Virneliz Fernandez-Vega Jill Ferguson Peter Hodder Prabhavathi Srinivasan Tara D Gonzalez Hugh Rosen Brian J Bahnson Benjamin F Cravatt |
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| Institution: | 1. The Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;2. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;3. The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;4. Lead Identification Division, Molecular Screening Center, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States;5. Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States;6. Department of Chemistry & Biochemistry, University of Delaware, Newark, DE 19716, United States |
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| Abstract: | Lipoprotein-associated phospholipase A2 (Lp-PLA2 or PLA2G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA2 has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA2 have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA2 inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA2 and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA2 in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA2 function in biological systems. |
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