Research Network for Metals in Medicine

 

 

Professor David Fairlie

Position: Deputy Head, Division of Structural Biology and Chemistry

Affiliation: Institute for Molecular Bioscience, University of Queensland

Postal Address:
Institute for Molecular Bioscience
The University of Queensland
St Lucia Q 4072
AUSTRALIA

Phone: +61 (07) 3346 2989
Fax: +61 (07) 3346 2101
Email: d.fairlie@imb.uq.edu.au
Webpage: http://www.imb.uq.edu.au/index.html?id=11696


Research Profile

We are mainly interested in metals as therapeutic targets in medicine, but have also had some success with metal-based therapies. As therapeutic targets for potential drugs, we have been working with :

(a) Metalloproteases, which use a Zn2+ ion to catalyse the hydrolysis of a peptide bond. They control both intracellular and extracellular peptide cleavages during numerous physiological processes, including digestion, fertilization, growth, differentiation, cell signalling and migration, immunological defence, wound healing, protein turnover and general 'housekeeping' functions, and are vital in the propagation of many disease processes. Selective inhibition of metalloproteases is increasingly being targeted for the treatment of cancers; parasitic and viral infections, inflammatory, immunological, and respiratory conditions; cardiovascular and degenerative disorders. Inhibitors of Angiotensin Converting Enzyme are examples of blockbuster drugs. We have analyzed crystal structures for 121 inhibitors and 1 substrate complexed with 20 metalloproteases and found a common beta strand peptide backbone conmformation is recognized in substrates and inhibitors by all metalloproteases, suggesting generic approaches to the development of (beta-strand mimicking) potent and selective inhibitors for metalloproteases. In a different context we have developed mimics of alpha helices that bind to metalloproteins, including metalloproteases, and can potentially trap endogenous metal ions using this approach.

(b) Inflammation and phospholipases A2, calcium enzymes that are responsible for cleaving esters of membrane phospholipids to arachidonic acid. We have developed some of the most potent and the most selective inhibitors of secretory PLA2 (types IIa and V) as potent antiinflammatory agents in vivo, demonstrating this as a viable approach for the treatment of arthritis, inflammatory bowel disease, ischemia-reperfusion injury, stroke, period pain and a range of other disease indications. A compound is entering clinical trials in 2004.

(c) Metals and Neurodegenerative Diseases. In the case of Alzheimers disease, the accepted origin of neurotoxicity and amyloid plaques is the 42-residue peptide called beta amyloid peptide (Ab). We demonstrated that this peptide has a high affinity for Cu, which potentiates neurotoxicity, and showed the first example of a beneficial effect of metal chelators on Ab-induced neurotoxicity, a result that is now the basis for clinical trials of copper-chelators for the treatment of Alzheimer's disease.

(d) Metal Drugs in Inflammation. Over 15 years ago we demonstrated novel antiinflammatory properties for Zn-based compounds that have an unusual two dimensional lattice structure, enabling their penetration of skin and other membranes. One compound, in a new patented microfine form, is currently being used by over 10,000 troops in Iraq for sun protection and treatment of sun-activated herpes simplex virus (cold sores) and is marketed throughout USA . Clinical studies have also been undertaken for its use as a metal-based medicine for the treatment of inflammatory conditions and viral infections.


Selected Publications

  1. Glenn, M. P.; Kelso, M. J.; Tyndall, J. D. A.; Fairlie, D. P. Conformationally Homogeneous Cyclic Tetrapeptides : Useful Three Dimensional Scaffolds J. Am. Chem. Soc. 2003, 125, 640-641.
  2. Kelso, M. J.; Hoang, H. N.; Oliver, W. N.; Sokolenko, N.; March, D. R.; Appleton, T. G.; Fairlie, D. P. A Cyclic Metallopeptide That Induces Alpha Helicity In Short Peptide Fragments of Thermolysin. Angew Chem, Int. Edit. 2003, 42, 421-424.
  3. Reid, R. C.; Abbenante, G.; Taylor, S. M.; Fairlie, D. P. A Convergent Solution Phase Synthesis of the Macrocycle, Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a Potent New Anti-Inflammatory Drug. J. Org. Chem. 2003, 68, 4464-4471.
  4. Hansford, K. A.; Reid, R. C.; Clark, C. I.; Tyndall, J. D. A.; Whitehouse, M. W.; Guthrie, T.; McGeary, R. P.; Schafer, K.; Martin, J. L.; Fairlie D. P. D-Tyrosine As A Chiral Precursor To Potent Inhibitors Of Human Non-Pancreatic Secretory Phospholipase A2 (IIa) With Anti-Inflammatory Activity. ChemBioChem. 2003, 4, 181-185.
  5. Arumgam, T. V.; Arnold, N.; Proctor, L. M.; Newman, M.; Reid, R. C.; Hansford, K. A.; Fairlie, D. P.; Shiels, I. A.; Taylor, S. M. Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selective inhibitors, and an LTC4 receptor antagonist. Br. J. Pharmacol. 2003, in press.
  6. Lucke, A. J.; Tyndall, J. D. A.; Singh, Y.; Fairlie, D. P. Designing supramolecular structures from models of cyclic peptide scaffolds with heterocyclic constraints, J. Molecular Graphics and Modelling 2003, 21, 341-355.
  7. Warrener, R.; Beamish, H.; Burgess, A.; Waterhouse, N. J.; Giles, N.; Fairlie, D. P.; Gabrielli, B. Tumour cell specific cytotoxicity by targeting cell cycle checkpoints. FASEB J. 2003, in press.
  8. Arumugum, T. V.; Shiels, I. A.; Strachan, A. J.; Abbenante, G.; Fairlie, D. P.; Taylor, S. M. A Small Molecule Antagonist of C5a Receptors Protects Kidneys From Ischaemia-Reperfusion Injury in Rats, Kidney International 2003, 63, 134-142.
  9. Williamson, A. L.; Brindley, P. J.; Abbenante, G.; Datu, B. J. D.; Prociv, P.; Berry|, C.; Girdwood, K.; Pritchard, D. I.; Fairlie, D. P.; Hotez, P. J.; Zhan, B.; Loukas, A. Hookworm Aspartic Protease, Na-APR-2, Cleaves Human Hemoglobin and Serum Proteins in a Host-Specific Fashion, J. Infect. Diseases 2003, 187, 484-494.
  10. Stoermer, M. J.; Butler, D. N.; Warrener, R. N.; Weerasuria, K. D. V.; Fairlie, D. P. Cycloadditions of Isobenzofuran to a Constrained Template Bearing Neighboring Dienophiles, Chem. Eur. J. 2003, 9, 2068-2071.
  11. Reid, R. C.; Kelso, M. J.; Scanlon, M. J.; Fairlie, D. P. Conformationally Constrained Macrocycles That Mimic Tripeptide Beta Strands In Water and Aprotic Solvents, J. Am. Chem. Soc. 2002, 124, 5673-5683.
  12. Kelso, M. J.; Hoang, H. N.; Oliver, W. N.; Sokolenko, N.; March, D. R.; Appleton, T. G.; Fairlie, D. P. A Cyclic Metallopeptide That Induces Alpha Helicity In Short Peptide Fragments of Thermolysin. Angew. Chem. Int. Edit. 2002, in press.
  13. Glenn, M. P.; Pattenden, L. K.; Reid, R. C.; Tyssen, D. P.; Tyndall, J. D. A.; Birch, C. J.; Fairlie, D. P. Beta strand mimicking macrocyclic amino acids. Templates for protease inhibitors with antiviral activity. J. Med. Chem. 2002, 45, 371-381.
  14. Singh, Y.; Stoermer, M. J.; Lucke, A. J.; Glenn, M. P.; Fairlie, D. P. Regioselective Synthesis of Two Antiparallel Loops on a Macrocyclic Scaffold Constrained by Oxazoles and Thiazoles. Organic Letters 2002, 4, 3367-70.
  15. Woodruff, T. M.; Strachan, A. J.; Dryburgh, N.; Shiels, I. A.; Reid, R. C.; Fairlie, D. P.; Taylor, S. M. Anti-Arthritic Activity of an Orally Active C5a Receptor Antagonist Against Antigen-Induced Monoarticular Arthritis in the Rat. Arthritis and Rheumatism 2002, 46, 2476-85.
  16. Williamson, A. L.; Abbenante, G.; Brindley, P. J.; Prociv, P.; Girdwood, K.; Berry, C.; Pritchard, D. I.; Fairlie, D. P.; Hotez, P. J.; Dalton, J. P.; Loukas, A. Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its contribution to host specificity. FASEB J. 2002, 16, 1458- 1460.
  17. Glenn, M. P.; Fairlie, D. P. Mimetics of the Peptide Beta-Strand. Mini Reviews in Medicinal Chemistry 2002, 2, 433-445.
  18. Cusack, R. M.; Grondahl, L.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R. Cyclic Octapeptides Containing Thiazole. Effect of stereochemistry and degree of flexibility on calcium binding properties. J. Chem. Soc. Perkin Trans. 2 2002, 556-563.
  19. Lucke, A. J.; Tyndall, J. D. A.; Singh, Y.; Fairlie, D. P. Designing supramolecular structures from models of cyclic peptide scaffolds with heterocyclic constraints. J. Molecular Graphics and Modelling 2002, 5344, 1-15.
  20. Arumugum, T. V.; Shiels, I. A.; Woodruff, T. M.; Reid, R. C.; Fairlie, D. P.; Taylor, S. M. Protective Effect of a New C5a Receptor Antagonist Against Ischaemia-Reperfusion Injury in the Rat Small Intestine. J. Surg. Res. 2002,103, 260-267.
  21. Kukuy E. L.; John, R.; Szabolcs M. J.; Ma, N.; Schuster, M.; Cannon, P. J.; Fairlie, D. P.; Edwards, N. M. Phospholipase A2 inhibitor attenuates NOx production and myocardial damage in the cardiac allograft. J. Heart Lung Transplant. 2002, 21, 133.
  22. Kelso, M. J.; Fairlie, D. P. Current Approaches To Peptidomimetics in "Molecular Pathomechanisms And New Trends In Drug Research" Eds. G. Keri, J. McMahon, I. Toth; Harwood Academic Publishers, The Netherlands, 2002 in press.
  23. Singh, Y.; Sokolenko, N.; Kelso, M. J.; Gahan, L. C.; Abbenante, G.; Fairlie, D. P. Novel Conical, Cylindrical, and Macrocyclic Peptides From The Cyclooligomerization Of Thiazole Amino Acids. J. Am. Chem. Soc. 2001, 123, 333-334.
  24. 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.
  25. Brindley, P.J., Kalinna, B.H., Wong, J.Y.M., Bogitsh, B.J., King, L.T., Smyth, D.J., Verity, C.K., Abbenante, G., Brinkworth, R.I., Fairlie, D.P., Smythe, M.L., Milburn, P.J., Bielfeldt-Ohman, H., Zheng, Y.; McManus, D.P. Proteolysis of human hemoglobin by schistosome cathepsin D. Molecular and Biochemical Parasitology 2001,112, 103-112.
  26. Cain S. A.; Woodruff, T. M.; Taylor, S. M.; Fairlie, D. P.; Sanderson, S. D.; Monk, P. N. Modulation of ligand selectivity by mutation of the first extracellular loop of the human C5a receptor. Biochem. Pharmacol. 2001, 61, 1571-1579.
  27. Woodruff, T. M.; Strachan, A. J.; Sanderson, S.; Monk, P. N.; Wong, A. K.; Fairlie, D. P.; Taylor, S. M. Species dependence for binding of small molecule agonists and antagonists of the C5a receptor on polymorphonuclear leukocytes. Inflammation 2001, 25, 171-7.
  28. Abbenante, G.; Leung, D.; Bond, T.; Fairlie, D. P. An efficient Fmoc strategy for the rapid synthesis of peptide para-nitroanilides Letters in Peptide Science 2001, 7, 347-351.
  29. Appleton, T. G.; Fairlie, D. P.; Hoang, H.; Kelso, M.; March, D.; Oliver, W. Control of peptide conformation by palladium(II) coordination. J. Inorg. Biochem. 2001, 86, 127.
  30. Tyndall, J. D. A.; Fairlie, D. P. Macrocycles Mimic The Extended Peptide Conformation Recognized By Aspartic, Serine, Cysteine and Metallo Proteases. Curr. Med. Chem. 2001, 8, 893- 907.
  31. Strachan, A. J.; Shiels, I. A.; Reid, R. C.; Fairlie, D. P.; Taylor, S. M. Inhibition Of Immune- Complex Mediated Dermal Inflammation In Rats Following Either Oral Or Topical Administration Of A Small Molecule C5a Receptor Antagonist. Br. J. Pharmacol. 2001, 134, 1778-1786.
  32. Kelso, M. J.; Hoang, H. N.; Appleton, T. G.; Fairlie, D. P. The First Solution Stucture Of A Single Alpha Helical Turn. A Pentapeptide Alpha-Helix Stabilised By A Metal Clip. J. Am. Chem. Soc. 2000, 122, 10488-10489.
  33. Rauk, A.; Armstrong, D. A.; Fairlie, D. P. Is oxidative damage by beta amyloid and prion peptides mediated by hydrogen atom transfer from glycine alpha carbon to methionine sulfur within beta sheets? J. Am. Chem. Soc. 2000, 122, 9761-9767.
  34. Leung, D.; Abbenante, G.; Fairlie, D. P. Protease Inhibitors : Current Status and Future Prospects. J. Med. Chem.. 2000, 43, 305-341.
  35. Tyndall, J. D. A.; Reid, R. C.; Tyssen, D. P.; Jardine, D. K.; Todd, B.; Passmore , M.; March, D. R.; Pattenden, L. K.; Bergman, D. A.; Alewood, D.; Hu, S-H.; Alewood, P. F.; Birch, C. J.; Martin, J. L.; Fairlie, D. P. Synthesis, Stability, Antiviral Activity, and Protease-Bound Structures of Substrate- Mimicking Constrained Macrocyclic Inhibitors of HIV-1 Protease. J. Med. Chem. 2000, 43, 3495- 3504.
  36. 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.
  37. Strachan, A. J.; Woodruff, T. M.; Haaima, G.; Fairlie, D. P.; Taylor, S. M. A New Small Molecule C5a Receptor Antagonist Inhibits the Reverse-Passive Arthus Reaction and Endotoxic Shock in Rats. J. Immunol. 2000, 164, 6560-6565.
  38. Qui, L.; Burgess A.; Fairlie, D. P.; Leonard, H.; Parsons, P. G.; Gabrielli, B. G. Histone Deacetylase Inhibitors Trigger a G2 Checkpoint in Normal Cells That Is Defective in Tumor Cells. Mol. Biol. Cell 2000, 11, 2069-2083.
  39. Haynes, D. H.; Harkin, D. G.; Bignold, L. P.; Hutchens, M. J.; Taylor, S. M.; Fairlie, D. P. Inhibition of C5a-induced neutrophil chemotaxis and macrophage cytokine production in vitro by a new C5a receptor antagonist. Biochem. Pharm. 2000, 60, 729-733.
  40. Andrews, K. T.; Walduck, A.; Kelso, M. J.; Fairlie, D. P.; Saul, A.; Parsons, P. G. Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents. Int. J. Parasitology 2000, 30, 761-768.
  41. Poulsen, S-A.; Watson, A. A.; Fairlie, D. P.; Craik, D. J. Solution Structures In Aqueous SDS Micelles of Two Amyloid Beta-Peptides AB(1-28) Mutated At The Alpha-Secretase Cleavage Site (K16E, K16F). J. Struct. Biol. 2000, 130, 142-152.
  42. Abbenante, G.; Kovacs, D. M.; Leung, D. L.; Craik, D. J.; Tanzi, R. E.; Fairlie, D. P. Inhibitors of Beta-Amyloid Formation Based On the Beta-Secretase Cleavage Site. Biochem. Biophys. Res. Com. 2000, 268, 133-135.
  43. Cusack, R. M.; Grondahl, L.; Abbenante, G.; Fairlie, D. P.; Gahan, L. C.; Hanson, G. R.; Hambley, T. W. Conformations of Cyclic Octapeptides and The Influence of Heterocyclic Ring Constraints upon Calcium Binding. J. Chem. Soc. Perkin Trans. 2, 2000, 323-331.
  44. Atwood, C.S., Scarpa, R.C., Huang, X., Moir, R.D., Jones, W.D., Fairlie, D.P., Tanzi, R.E. and Bush, A.I. Characterization of Copper Interactions with Alzheimer AB Peptides- Identification of an Attomolar Affinity Copper Binding Site on AB1-42. J. Neurochem. 2000, 75, 1219-1233.

Facilities

  • computer assisted drug design facilities
  • enzyme assays
  • animal assays especially for inflammation and cancer

International Linkages

Ashely Bush, Harvard
Mike Kelso, SCRIPPS
Ed Dennis, UC SanDiego
Pure Lip Pharmaceuticals, Los Angeles