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Professor David P Fairlie**
Institute for Molecular Bioscience
University of Queensland
Brisbane, Qld 4072
Email: d.fairlie@imb.uq.edu.au
Tel: +61-7-3346-2989
Fax: +61-7-3346-2990
Homepage: http://www.imb.uq.edu.au/index.html?id=11696

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.
Professor Paul Young, University of Queensland, Australia
Dr Reik Löser, University of Bonn, Germany
Dr. Gloria Ruiz Gómez, Universidad de Almería, Spain
Leung D. Abbenante G. Fairlie DP. Protease Inhibitors : Current Status and Future Prospects, J. Med. Chem. 2000, 43, 305-341.

Fairlie DP. Tyndall JDA. Reid R C. Wong AK. Abbenante G. Scanlon MJ. March DR. Bergman DA. Chai CLL. Burkett BA. 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 MJ. Abbenante G. Martin JL. Young P. Fairlie DP. 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 KJ. Stoermer MJ. Fang N-X. Tyndall JDA. Young PR. Fairlie DP. Enzymatic Characterisation and Homology Model Of A Catalytically Active Recombinant West Nile Virus NS3 Protease. J. Biol. Chem. 2004, 279, 48535-48542.

Loughlin WA. Tyndall JDA. Glenn MP. Fairlie DP. Beta Strand Mimetics.
Chemical Reviews 2004, 104, 6085-6117; 2010 (110/6) PR32-69.

Tyndall JDA. Nall T. Fairlie DP. Proteases Universally Recognize Beta Strands In Their Active Sites Chemical Reviews 2005, 105, 973-1000; 2010 (110/6) PR1-31.

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

Chappell KJ. Stoermer MJ. Fairlie DP. Young PR. 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 JDA. Pattenden LK. Reid RC. Hu S-H. Alewood D. Alewood PF. Walsh T. Fairlie DP. Martin JL. Crystal Structures of Highly Constrained Substrate and Hydrolysis Products Bound to HIV-1 Protease.Implications for Catalytic Mechanism. Biochemistry 2008, 47, 3736-44.

Stoermer MJ. Chappell KJ. Liebscher S. Jensen CM. Gan CH. Gupta PK. Xu W-J. Young PR. Fairlie DP. 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.

Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT, Fairlie DP*. Modulating Human Proteinase Activated Receptor 2 With A Novel Antagonist (GB88) and Agonist (GB110). Br J Pharmacol. 2012, 165(5):1413-23.

Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY, Vesey DA, Fairlie DP*.
An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J. 2012, 26, 2877-2887.

Yau MK, Liu L, Fairlie DP. Towards Drugs for Protease-Activated Receptor 2 (PAR2). J Med Chem 2013, 56, 7477-7497.

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