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New approaches for dissecting protease functions to improve probe development and drug discovery

Abstract

Proteases are well-established targets for pharmaceutical development because of their known enzymatic mechanism and their regulatory roles in many pathologies. However, many potent clinical lead compounds have been unsuccessful either because of a lack of specificity or because of our limited understanding of the biological roles of the targeted protease. In order to successfully develop protease inhibitors as drugs, it is necessary to understand protease functions and to expand the platform of inhibitor development beyond active site–directed design and in vitro optimization. Several newly developed technologies will enhance assessment of drug selectivity in living cells and animal models, allowing researchers to focus on compounds with high specificity and minimal side effects in vivo. In this review, we highlight advances in the development of chemical probes, proteomic methods and screening tools that we feel will help facilitate this paradigm shift in drug discovery.

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Figure 1: Mechanism of substrate hydrolysis by the primary families of proteases.
Figure 2: Schematic presentation of the hit-to-lead process.
Figure 3: Activity-based probes report on tightly regulated protease activity.
Figure 4: Chemical tools to study protease function and to measure target inhibition.

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Acknowledgements

The authors thank Dr. Christopher Kirk for his comments and suggestions. This work was funded by NIH grants R01 EB005011 and R01 AI078947 (to M.B.) and a Rubicon grant from The Netherlands Organization for Scientific Research (NWO) (to M.V.).

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Deu, E., Verdoes, M. & Bogyo, M. New approaches for dissecting protease functions to improve probe development and drug discovery. Nat Struct Mol Biol 19, 9–16 (2012). https://doi.org/10.1038/nsmb.2203

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