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Proteases are a class of enzymes that play a pivotal role in many patho-physiological processes and impairment of their regulation is the cause of many cardiovascular, inflammatory and neurodegenerative diseases. Moreover, proteolysis is necessary for the pathogenesis of many infectious microorganisms and for the proliferation and invasiveness of cancer cells.
Proteases are validated drug targets for the treatment of highly-demanding pathologies. Angiotensin-Converting Enzyme, the HIV protease, and the proteasome are targeted by specific inhibitors to treat hypertension, HIV infection and multiple myeloma, respectively.
There is still huge potential for therapeutic intervention by proteases. But their accessibility to the drug discovery process is often hampered by the complex biochemistry of the enzymes themselves that require dedicated strategies for functional expression and post-translational processing.
At Axxam, the Protease Platform is a streamlined research program that aims to express, purify and functionally characterize the human proteases. We particularly focus on those enzymes targeted to the secretory pathway, because of their modulatory role on bioactive molecules and their accessibility to various drug delivery mechanisms.
The process integrates bioinformatic, molecular and biochemical experimental approaches and aims to support the drug discovery process by providing HTS-compatible assays to identify novel inhibitors and to profile the selectivity of lead compounds.
So far, the Axxam Protease Platform has achieved:
- creation of a database for human functional proteases
- genome-scale expression analysis of human proteases
- creation of a repository of full-length genes encoding for proteases
- growth, transfection and recombinant expression of human proteases in insect cells in a miniaturized format
- high-throughput automated purification for secreted proteases
- HTS-compatible assay development for proteases with a fluorescence-based readout in 384-MTP format
- identification of specific substrates by screening a 500-peptide library
- miniaturization, parallelization and automation along the entire process.
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