Protease targets have long been considered ‘druggable’ and there are a significant number of successful drugs already in clinical use that function as selective inhibitors of key disease-associated proteases. It is becoming increasingly clear that many of these enzymes represent key checkpoints in various cellular pathways, and that loss of control of their activity frequently leads to the triggering and exacerbation of diseases such as cancer, respiratory diseases, inflammation and infection (bacterial, parasitic and viral).
The development of peptide-based protease inhibitors and their use in ‘activity-based profiling’ is one of the longest-established research themes within the School, and has become one of the most important technologies in global protease research. This foundation has underpinned the development of an extensive research programme, which currently includes the development of ‘activity-based profiling’ approaches for the identification and characterisation of novel protease targets and semi-quantitative analysis of alterations in cellular proteolytic signatures.
A key focus within the theme is the development of novel inhibitor strategies (both small molecule and macromolecular biologics) for the development of inhibitors towards cysteine proteases implicated in cancer (cysteine cathepsins and ubiquitin-specific proteases). This work is underpinned by basic research into the roles of these proteases in disease both within the school and with international collaborators.
Other research priorities within the theme include the delineation and inhibition of proteases involved in the destruction of host molecules of innate defence, the development of anti-biofilm strategies using metallopeptidase-directed inhibitors and the identification and modulation of channel-activating proteases. There is also a strong interest in the Identification and application of protease inhibitors from venoms.
Research from this theme has led to many key developments including the development of activity-based profiling, More recently, an approach was developed to isolate macromolecular biologic inhibitors (including antibodies) of cysteine proteases, which have successfully been out-licensed to Fusion Antibodies Ltd. and are currently in late stage preclinical development as angiostatic and anti-metastatic lead compounds.
The individual research programmes are supported by grant income from various funding sources including RC-UK, charities and government commercialisation funding. The multi-disciplinary nature of the work is also supported by extensive collaborations with leading research groups in Canada, France, Germany, the US and China, including the University of Alberta, The Scripps Institute, University of British Columbia, Dana Faber Cancer Institute, Memorial Sloan Kettering Cancer Centre and the Chinese Medical University (Shenyang).