An Activity-Based Imaging Probe for the Integral Membrane Hydrolase KIAA1363

摘要

Activity-based protein profiling (ABPP) is a chemical pro-teomic platform for characterizing enzyme activities in native biological systems. Original small-molecule probes for ABPP were designed to target large numbers of enzymes that share mechanistic and/or structural features. These efforts have yieled activity-based probes for many enzyme classes, including serine and cysteine hydrolases, oxidoreduc-tases, metalloproteases, histone deacetylases, kinases, and glycosidases. ABPP has been applied to discover enzyme activities that are deregulated in biological processes such as cancer and infectious disease. Configuring ABPP to operate in a competitive mode has further enabled the development of selective inhibitors to probe the function of disease-relevant enzymes in cell and animal models. As biological studies using ABPP have evolved, the need for target-selective activity-based probes has also become apparent. The specificity of such probes opens up new biological applications, including direct spatial and temporal visualization of active enzymes in cells and tissues. While attractive in principle, the development of protein-selective, activity-based imaging probes poses substantial technical challenges. Such a probe should ideally possess several features, including high selectivity for a single enzyme target, a reporter tag for imaging the probe-labeled enzyme, and suitable cell permeability and pharmacokinetic properties for in vivo studies. These objectives have, so far, been realized for only a handful of probes that label proteolytic enzymes and whether they can be achieved for probes that target additional types of enzymes remains unknown.