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Emerging principles in protease-based drug discovery

Abstract

Proteases have an important role in many signalling pathways, and represent potential drug targets for diseases ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses. Although inhibitors of well-established protease targets such as angiotensin-converting enzyme and HIV protease have shown substantial therapeutic success, developing drugs for new protease targets has proved challenging in recent years. This in part could be due to issues such as the difficulty of achieving selectivity when targeting protease active sites. This Perspective discusses the general principles in protease-based drug discovery, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets.

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Figure 1: Tetrahedral intermediates formed during peptide cleavage by proteases.
Figure 2: Active site, exosite and allosteric site.
Figure 3: Probing protease active sites.

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Acknowledgements

The Salvesen laboratory is supported by National Institutes of Health grants CA69381, RR20843 and NS61758, and by the Human Frontier Science Program grant RGP0024. The Drag laboratory is supported by the Foundation for Polish Science and the State for Scientific Research Grant N N401 042838 in Poland. The authors would like to thank E. Madison, B. Turk and the members of their laboratories for helpful discussions.

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Correspondence to Marcin Drag or Guy S. Salvesen.

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Glossary

Active site

Region in the enzyme in which the primary substrate binding site is localized and catalysis occurs. Usually the active site is on the surface of the enzyme and is made up of pockets defined by protein surfaces, which are responsible for the specific binding of the substrate amino acid residues next to the scissile bond.

Allosteric site

Region of the enzyme that does not participate directly in substrate recognition and processing. Through the ability to interact with specific modulators (proteins or small molecules) the allosteric site enhances or inhibits substrate to product transition through conformational changes in the enzyme.

Exosite

Region of the enzyme distant from the active site that is responsible for specific substrate–enzyme interactions. Exosite interactions influence the rates of catalysis, and sometimes of substrate specificity, of a given protease. Classic examples are the recognition of fibrinogen by thrombin, ubiquitin recognition by ubiquitin-specific peptidases (deubiquitylating enzymes or DUBs), and small ubiquitin-like modifier (SUMO) recognition by SUMO-specific proteases (SENPs).

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Drag, M., Salvesen, G. Emerging principles in protease-based drug discovery. Nat Rev Drug Discov 9, 690–701 (2010). https://doi.org/10.1038/nrd3053

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