Emerging principles in protease-based drug discovery

Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 09/2010; 9(9):690-701. DOI: 10.1038/nrd3053
Source: PubMed


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.


Available from: Marcin Drag
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    • "Several successful strategies have been applied towards the development of currently in use protease inhibitors to treat hypertension, HIV, cancer, diabetes and coagulation disorders (Drag & Salvesen, 2010). Characterization of the role of proteases in disease and also their precise mechanism of action was essential for these drug discoveries. "
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    • "For example, in many cancers, development of protease inhibitor-based drugs has been challenging due to the difficulty in selectively targeting the active sites. In such cases, allosteric sites could be targeted to achieve the goals [17]. Malaria parasite is the most important member of the parasites of phylum Apicomplexa, which invade the host cell and reside in intracellular niche that is protected from host defenses and provides a rich source of nutrient. "
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