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.

Download full-text


Available from: Marcin Drag
  • Source
    • "Caspases may be inhibited by the Inhibitor of apoptosis proteins (IAPs). whereas an effector caspase contains only 20–30 residues in its prodomain [9]. In addition, only initiator caspases contain a caspase recruitment domain (CARD) or death effector domain (DED) preceding the catalytic domain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, , BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.
    Full-text · Article · Aug 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteolysis within the lipid bilayer is poorly understood, in particular the regulation of substrate cleavage. Rhomboids are a family of ubiquitous intramembrane serine proteases that harbour a buried active site and are known to cleave transmembrane substrates with broad specificity. In vitro gel and Förster resonance energy transfer (FRET)-based kinetic assays were developed to analyse cleavage of the transmembrane substrate psTatA (TatA from Providencia stuartii). We demonstrate significant differences in catalytic efficiency (kcat/K0.5) values for transmembrane substrate psTatA (TatA from Providencia stuartii) cleavage for three rhomboids: AarA from P. stuartii, ecGlpG from Escherichia coli and hiGlpG from Haemophilus influenzae demonstrating that rhomboids specifically recognize this substrate. Furthermore, binding of psTatA occurs with positive cooperativity. Competitive binding studies reveal an exosite-mediated mode of substrate binding, indicating allostery plays a role in substrate catalysis. We reveal that exosite formation is dependent on the oligomeric state of rhomboids, and when dimers are dissociated, allosteric substrate activation is not observed. We present a novel mechanism for specific substrate cleavage involving several dynamic processes including positive cooperativity and homotropic allostery for this interesting class of intramembrane proteases.
    Full-text · Article · Jul 2014 · The EMBO Journal
    • "Correspondence: Dr. Marko Fonovic, Department of Biochemistry Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia E-mail: Fax: +386-1-477-3772 Abbreviations: ECM, extracellular matrix; MMP, matrix metalloproteinase ; OA, osteoarthritis; RA, rheumatoid arthritis; SMC, smooth muscle cell; uPA, urokinase plasminogen activator neurodegenerative diseases [2] [3] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since their discovery, cysteine cathepsins were generally considered to be involved mainly in the nonspecific bulk protein degradation that takes place within the lysosomes. However, it has become clear that their proteolytical activity can also influence various specific pathological processes such as cancer, arthritis and atherosclerosis. Furthermore, their localisation was found not to be limited strictly to the lysosomes. In the light of those findings it is not surprising that cysteine cathepsins are currently considered as highly relevant clinical targets. Moreover, recent development of proteomic-based methods for identification of novel physiological substrates of proteases provides a major opportunity also in the field of cysteine cathepsins. In this review, we will therefore present cysteine cathepsin roles in disease progression and discuss their potential relevance as prognostic and diagnostic biomarkers. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2014 · PROTEOMICS - CLINICAL APPLICATIONS
Show more