Review Article | Published:

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

Nature Structural & Molecular Biology volume 19, pages 916 (2012) | Download Citation

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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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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Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

    • Edgar Deu
    • , Martijn Verdoes
    •  & Matthew Bogyo
  2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.

    • Matthew Bogyo

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthew Bogyo.

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https://doi.org/10.1038/nsmb.2203

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