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Welcome to the Australian 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)
Institute for Molecular Bioscience
University of Queensland
Brisbane, Qld 4072, Australia
Tel +61-7-3346-2989
Fax +61-7-3346-2101 or 2103
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 associated with human disease. We have documented the almost universal protease recognition of substrates/inhibitors in the extended or beta strand conformation, and identified a number of 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 have performed some of the first studies to develop inhibitors of the NS3 proteases of Dengue and West Nile Viruses, these being crucial for viral replication, and we have been refining new generation potent and selective nanomolar inhibitors of HIV proteases with extremely low resistance against HIV-1 and HIV-2 viruses. We have developed potent and selective nanomolar 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, reporting the first cell permeable sub-micromolar inhibitors of the beta secretase enzyme involved in formation of beta amyloid peptide thought to be pathogenic in Alzheimer's disease, and are currently developing inhibitors of human complement convertases, and antagonists of human protease activated receptors, associated with inflammatory disease.

Current Collaborators: (max 0-20) - Please invite your collaborators to submit an entry too.
Name, Institution, country
Dr. Paul Young, University of Queensland, Australia....

Selected Protease Publications: (max 0-5)
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.; Abbenante, G.; Fairlie, D. P. "Protease Inhibitors : Current Status and Future Prospects", J. Med. Chem. 2000, 43, 305-341.

Abbenante, G.; Kovacs, D. M.; Leung, D. L.; Craik, D. J.; Tanzi, R. E.; Fairlie, D. P. "Inhibitors of b-Amyloid Formation Based On the b-Secretase Cleavage Site" Biochem. Biophys. Res. Com. 2000, 268, 133-135.

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.

Reid, R. C.; Kelso, M. J.; Scanlon, M. J.; Fairlie, D. P. Conformationally Constrained Macrocycles That Mimic Tripeptide b-Strands In Water and Aprotic Solvents, J. Am. Chem. Soc. 2002, 124, 5673-5683.

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