Proteases as therapeutics

Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94131, USA.
Biochemical Journal (Impact Factor: 4.4). 04/2011; 435(1):1-16. DOI: 10.1042/BJ20100965
Source: PubMed


Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications.

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    • "The lower affinity of proteases for their substrates and their catalytic activity may help them remain therapeutic, even in the presence of antigen sinks, and achieve higher tissue penetration. To date, clinical applications of proteases have been exclusively based on the specificity of natural proteases to catalyze the hydrolysis of their native substrates to therapeutic effect (Craik et al., 2011), in many instances as enzyme replacement therapy such as for many of the coagulation factors. Although it would be very attractive to widen the therapeutic scope of proteases, the requirements in terms of activity and specificity are demanding. "
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    ABSTRACT: The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro. MMP-8 degraded human IL-13 most efficiently in vitro and ex vivo in human IL-13 transgenic mouse bronchoalveolar lavage. Hence, MMP-8 is a therapeutic protease lead against IL-13 for inflammatory conditions whereby reported genetic and genomics data suggest an involvement of MMP-8. This work describes the first exploitation of human enzyme promiscuity for therapeutic applications, and reveals both starting points for protease-based therapies and potential new regulatory networks in inflammatory disease.
    Chemistry & biology 11/2015; DOI:10.1016/j.chembiol.2015.09.013 · 6.65 Impact Factor
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    • "Proteases control important biological processes, such as DNA replication, cell-cycle progression, cell proliferation, differentiation, and apoptosis through their ability to initiate , modulate, and terminate a variety of essential cellular functions by the processing of peptides and proteins [1]. In addition to their role in nature, proteases also serve as essential tools in industrial applications as well as biomedical research [2] [3]. There exist a number of methods to characterize and engineer proteases and protease substrates [4] [5]. "
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    ABSTRACT: Proteases are involved in many biological processes and have become important tools in biomedical research and industry. Technologies for engineering and characterization of, for example, proteolytic activity and specificity are essential in protease research. Here, we present a novel method for assessment of site-specific proteolysis. The assay utilizes plasmid-encoded reporters that, upon processing by a co-expressed protease, confer antibiotic resistance to bacteria in proportion to the cleavage efficiency. We have demonstrated that cells co-expressing cleavable reporters together with tobacco etch virus protease (TEVp) could be discriminated from cells with non-cleavable reporters by growth in selective media. Importantly, the resistance to antibiotics proved to correlate with the substrate processing efficiency. Thus, by applying competitive growth of a mock library in antibiotic-containing medium, we could show that the substrate preferred by TEVp was enriched relative to less-efficient substrates. We believe that this simple methodology will facilitate protease substrate identification, and hold great promise for directed evolution of proteases and protease recognition sequences towards improved or even new functionality.
    Biotechnology Journal 01/2014; 9(1). DOI:10.1002/biot.201300234 · 3.49 Impact Factor
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    • "In general, proteases have been used therapeutically in four areas: the management of gastrointestinal disorders with orally administered agents, as anti-inflammatory agents, as thrombolytic agents for thromboembolic disorders, and as locally administered agents for wound debridement [10]. Since the first approval of a protease drug in 1978 (urokinase, a serine protease indicated for thrombolysis and catheter clearing), a further 11 drugs have been approved for therapeutic use by the US Food and Drug Administration (FDA) [3]. The majority of these are indicated for the treatment of blood disorders and include thrombolytics: alteplase, reteplase, and tenecteplase; and procoagulants: factor IX, factor VIIa, thrombin, and topical thrombin in bandages. "
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    ABSTRACT: Proteases have been used in medicine for several decades and are an established and well tolerated class of therapeutic agent. These proteases were sourced from mammals or bacteria that exist or have adapted to moderate temperatures (mesophilic organisms); however, proteases derived from organisms from cold environments—cold-adapted or psychrophilic proteases—generally have high specific activity, low substrate affinity, and high catalytic rates at low and moderate temperatures. Made possible by greater flexibility, psychrophilic enzymes interact with and transform the substrate at lower energy costs. Cold-adapted proteases have been used in a wide range of applications, including industrial functions, textiles, cleaning/hygiene products, molecular biology, environmental bioremediations, consumer food products, cosmetics, and pharmaceutical production. In addition to these applications, they have also shown promise as therapeutic modalities for cosmeceutical applications (by reducing glabellar [frown] lines) and a number of disease conditions, including bacterial infections (by disrupting biofilms to prevent bacterial infection), topical wound management (when used as a debridement agent to remove necrotic tissue and fibrin clots), oral/dental health management (by removing plaque and preventing periodontal disease), and in viral infections (by reducing the infectivity of viruses, such as human rhinovirus 16 and herpes simplex virus). Psychrophilic proteases with greater activity and stability (than the original organism-derived variant) have been developed; this coupled with available manufacturing recombinant production techniques suggests that cold-adapted proteases have a promising future as a distinct therapeutic class with diverse clinical applications.
    06/2013; 2(1). DOI:10.1007/s40121-013-0002-x
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