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Welcome to the International Protease Network. We invite all parties interested in proteases, their inhibitors, or their receptors to contribute/update relevant information to this website, which you can join by submitting to the Network Administrator a simple one page description of your protease interests. Your entry may be edited if it is not precisely in the format below:

Professor David P. Fairlie (JPEG picture if available)
Divison of Chemistry and Structural Biology
Institute for Molecular Bioscience
University of Queensland
Brisbane, Qld 4072, Australia
Tel +61-7-3346-2989
Fax +61-7-3346-2990
Email d.fairlie@imb.uq.edu.au
Links : http://www.imb.uq.edu.au/Fairlie.html

Protease Research: (max 1-2 paragraphs to total no more than 250 words)

We are interested in generic approaches to the design and synthesis of inhibitors of aspartic, serine, cysteine, metallo and threonine proteases as well as protease activated receptors associated with human disease. We have documented the common recognition by proteases of substrates/inhibitors in the extended or beta strand conformation, and identified successful approaches to creating potent protease inhibitors by mimicking the beta strand peptide conformation. More recently we have used protease inhibitors to map the flexible boundaries of protease active sites, information that cannot come from (static) crystal structures, and this is a promising new approach to optimising inhibitor selectivity. Our current work is directed at protease inhibitors without electrophilic, metal-binding, or transition state isosteres. On viral proteases we performed some of the first studies to develop inhibitors of the NS3 proteases of Dengue and West Nile Viruses, these proteases being crucial for viral replication, and we have refined new generation potent and selective inhibitors of HIV proteases with low resistance against HIV-1 and HIV-2 viruses. We have developed potent and selective inhibitors of parasite proteases such as Schistosomal and Hookworm cathepsins, enzymes that process human hemoglobin for blood-feeding worms. We have also targeted the inhibition of human proteases, including some associated with neurodegenerative diseases, cytokine production, formation of complement proteins, as well as nonpeptidic antagonists of human protease activated receptors associated with inflammatory, proliferative and cardiovascular diseases..


Current Collaborators: (max 0-20) - Please invite your collaborators to submit an entry too.
Name, Institution, country
Professor Paul Young, University of Queensland, Australia. Dr Reik Löser, University of Bonn, Germany. Dr. Gloria Ruiz Gómez, Universidad de Almería, Spain.

Selected Protease Publications: (max 0-10)
Leung, D.; Abbenante, G.; Fairlie, D. P. Protease Inhibitors : Current Status and Future Prospects, J. Med. Chem. 2000, 43, 305-341.

Fairlie, D. P.; Tyndall, J. D. A.; Reid, R. C.; Wong, A. K.; Abbenante, G.; Scanlon, M. J.; March, D. R.; Bergman, D. A.; Chai, C. L. L.; Burkett, B. A. "Conformational Selection Of Inhibitors and Substrates By Proteolytic Enzymes : Implications for Drug Design and Polypeptide Processing", J. Med. Chem. 2000, 43, 1271-1281.

Leung, D.; Schroder, K.; White, H.; Fang, N.-X.; Stoermer, M. J.; Abbenante, G.; Martin, J. L.; Young, P.; Fairlie, D. P. Activity Of Recombinant Dengue 2 Virus NS3 Protease In The Presence Of NS2B Cofactor, Small Peptide Substrates, And Inhibitors, J. Biol. Chem. 2001, 276, 45762-45771

Nall, T., Chappell, K. J., Stoermer, M. J., Ning-Xia Fang, Tyndall, J. D. A., Young, P. R., Fairlie, D. P. Enzymatic Characterisation and Homology Model Of A Catalytically Active Recombinant West Nile Virus NS3 Protease. J. Biol. Chem. 2004, 279, 48535-48542.

Loughlin, W. A.; Tyndall, J. D. A.; Glenn, M. P.; Fairlie, D. P. Beta Strand Mimetics. Chemical Reviews 2004, 104, 6085-6117.

Tyndall, J. D. A.; Nall, T.; Fairlie, D. P. Proteases Universally Recognize Beta Strands In Their Active Sites Chemical Reviews 2005, 105, 973-1000.

Abbenante, G.; Fairlie, D. P. Protease Inhibitors in the Clinic. Medicinal Chemistry 2005, 1, 71-104.

Chappell, K. J.; Stoermer, M. J.; Fairlie, D. P.; Young, P.R. Insights to Substrate Binding and Processing by West Nile Virus NS3 Protease through Combined Modelling, Protease Mutagenesis, and Kinetic Studies. J. Biol. Chem. 2006, 281, 38448-58.

Tyndall, J. D. A.; Pattenden, L. K.; Reid, R. C.; Hu, S.-H.; Alewood, D.; Alewood, P. F.; Walsh, T.; Fairlie, D. P.; Martin, J. L. Crystal Structures of Highly Constrained Substrate and Hydrolysis Products Bound to HIV-1 Protease. Implications for Catalytic Mechanism. Biochemistry 2008, 47, 3736-44.

Stoermer, M. J.; Chappell, K. J.; Liebscher, S.; Jensen, C. M.; Gan, C. H.; Gupta, P. K.; Xu, W-J.; Young, P. R.; Fairlie, D. P. Potent Cationic Inhibitors of West Nile Virus NS2B/NS3 Protease With Serum Stability, Cell Permeability and Antiviral Activity J. Med. Chem. 2008, 51, 5714-21.







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