New tools for dissecting protease function: implications for inhibitor design drug discovery and probe development

摘要

Proteases have long been considered targets for pharmaceutical development because of our deep understanding of their enzymatic mechanism and their regulatory roles in many pathologies. However, despite our ability to develop potent inhibitors, many clinical lead compounds have failed due either to a lack of specificity or a limited understanding of the biological roles of the targeted protease. In order to successfully develop protease inhibitors as drugs, it is necessary to first understand protease function and second, to expand the platform of inhibitor development beyond active site-directed design and in vitro optimization. Several newly developed technologies will enable much broader assessment of drug selectivity in living cells and in animal models, allowing for lead optimization to focus on compounds that show high specificity and minimal side effects in vivo. In this perspective, we highlight the current advances in the development of new chemical probes, proteomic methods, and screening tools that we feel will help facilitate this paradigm shift in drug discovery methods.