Proteases play a key role in a number of pathological processes. Disregulation of proteases has been shown to play a role in diseases such as rheumatoid arthritis, cardiovascular diseases, bacterial and viral infections, cancer or Alzheimer’s disease. Several protease inhibitors are already available as drugs. Of particular interest are the Angiotensin Converting Enzyme (ACE) inhibitors which successfully lower blood pressure and the recently introduced inhibitors of the Human Immunodeficiency Virus (HIV) protease, key elements in many  triple therapies to fight the HIV infection. While most inhibitors available today target ACE or the HIV protease, a recent analysis of the complete human genome reveals the existence of 500 – 600 different members of this enzyme family. Therefore the potential of proteases for drug discovery remains enormous, especially if one also takes into account the possibilities for therapeutic intervention offered by bacterial and viral proteases.

The major aim of the Expertise Program Proteases at the Novartis Institutes for BioMedical Research (NIBR) is to render protease-directed drug discovery more predictable and more efficient. To this end, all activities focussing on the molecular aspects of protease-directed drug discovery are integrated in the Expertise Program. Bioinformatics, molecular biology, enzymology, development of high-throughput screening assays, medicinal chemistry, crystallography, NMR spectroscopy  and molecular modelling are essential components of the group.

Traditionally, progress in the development of protease inhibitors has been hampered by two main hurdles: selectivity and oral bioavailability. To address selectivity, we systematically mine the human genome around proteases which have been shown to play a key role in diseases with high medical needs. This ensures that we know all members of  the protease subfamilies of interest. Then, using the most recent advances in screening technologies, we develop a panel of assays in which we can profile drug candidates. Profiling data guide lead optimization and ensure that  compounds selected for further development are selective. An other help to obtain selective inhibitors is provided by 3-dimensional structural information on our protease targets and counter-targets. Therefore we routinely solve the 3-dimensional structure of proteases with bound inhibitors and exploit this information using computer-assisted molecular design tools. The power of structural information in lead optimisation has been best exemplified with the extremely fast progress in the development of HIV protease inhibitors, which became available for the treatment of AIDS less than 10 years following the discovery of the viral enzyme. To obtain orally active protease inhibitors we focus on novel non-peptidic lead structures. In the past protease inhibitors have mainly been derived from the peptide substrate of the enzyme and have therefore retained a significant peptidic character which has precluded good oral bioavailability. We gain access to non-peptidic inhibitors by screening the Novartis compound collection with high throughput assays and by developing and exploiting novel lead discovery approaches such as fragment screening by NMR or X-ray.

The integration of  all activities focussing on the molecular aspects of protease-directed drug discovery in the Program, from the gene to a drug candidate, ensures a fast delivery of  high quality protease inhibitors to our Disease Areas, who are the centres of excellence for disease knowledge in the NIBR. The availability of the necessary skills in the Expertise Program allows us to remain highly innovative and competitive in protease-directed drug discovery.

Our Proteases Platform is located in Basel and headed by Sylvain Cottens.

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