Research Network for Metals in Medicine



Dr Kevin Barnham

Position: Senior Research Fellow (RD Wright Fellow)

Affiliation: Department of Pathology, The University of Melbourne

Postal Address:
Department of Pathology
The University of Melbourne
Victoria 3010

Phone: +61 (3) 8344 5867
Fax: +61 (3) 8344 4004

Research Profile

Kevin J Barnham holds an RD Wright, NH&MRC Fellowship within the Pathology Department at The University of Melbourne, his research interests include studying the effects that co-factors such as metal ions and membranes have on protein folding with particular applicability to the neurodegenerative diseases. This information is then used to develop therapeutic strategies for targeting these diseases. Strategies that include the development of metallo-complexes as potential therapeutics as detailed in the patent “Beta-Amyloid Peptide Inhibitors”; K. Barnham, T. McCarthy, S. Pallich, B. Matthews, R. Cherny (1999) Australia AU00/00886K His PhD (The University of Queensland; 1993) and post-doctoral studies (Birbeck College; The University of London; 1992-1995) were in bioinorganic chemistry with a particular emphasis on the synthesis and mechanistic studies of platinum anticancer drugs. These studies in collaboration with Prof. Sadler resulted in novel intermediates of Pt drugs being identified and synthesized. Between 1995-2000 he worked on determining protein structures by NMR with the aim of identifying potential drug targets at the Biomolecular Research Institute. In 2001 he joined the Pathology Department at the University of Melbourne as a Senior Research Fellow to investigate the role that metal ions play in neurodegenerative diseases and to elucidate the mechanisms causing Ab neuronal toxicity. He has characterized the metal binding sites on Ab and APP and provided new insights into the toxic mechanism of Ab. He has worked in close collaboration with Profs. Colin Masters (University of Melbourne) and Ashley Bush (MGH Havard) to identify, characterize and develop the use of metal chelators such clioquinol as potential therapeutics for AD.

Selected Publications

  1. Appleton T.G., Barnham K.J., Hall J.R., Mathieson M.T. Reactions of nitroplatinum complexes. 1. 15N and 195Pt NMR spectra of platinum(II) nitrite complexes. Inorg. Chem. 1991, 30(13), 2751-2756.
  2. Appleton T.G., Bailey A.J., Barnham K.J., Hall J.R. Aspects of the solution chemistry of trans-diammineplatinum(II) complexes. Inorg. Chem. 1992, 31(14), 3077-3082.
  3. Barnham K.J., Djuran M.I., Frey U., Mazid M.A., Sadler P.J. [Pd(CBDCA-O,O’)(NH3)2]: The Pd(II) analogue of a platinum anticancer drug (CBDCA=cyclobutane-1,1-dicarboxylate). J. Chem. Soc. Chem. Comm. 1994, 65-66.
  4. Barnham K.J., Djuran M.I., Murdoch P.D., Sadler P.J. Intermolecular displacement of S-bound L-methionine on platinum(II) by guanosine 5’-monophosphate. Implications for the mechanism of action of anticancer drugs. J. Chem. Soc. Chem. Comm. 1994, 721-722.
  5. Barnham K.J., Frey U., Murdoch P-D.S., Ranford J.D., Sadler P.J., Newell D.R. Pt(CBDCA-O)(NH3)2(L-Methionine-S)]: Ring-opened adduct of the anticancer drug Carboplatin (Paraplatin)- Detection of a similar complex in urine by NMR spectroscopy. J. Am. Chem. Soc. 1994, 116(24), 11175-11177.
  6. Barnham K.J., Bauer C.I., Djuran M.I., Mazid M.A., Rau T., Sadler P.J. Outer-sphere macrochelation in [Pd(en)(5’-GMP-N7)2].9H2O and [Pt(en)(5’-GMP-N7)2].9H2O: X-ray crystallography and NMR spectroscopy in solution. Inorg. Chem. 1995, 34, 2826-2832.
  7. Barnham K.J., Djuran M.I., Murdoch P-D.S., Ranford J.D., Sadler P.J. L-Methionine increases the rate of reaction of 5’-guanosine monophosphate with the anticancer drug cisplatin: Mixed ligand adducts and reversible methionine binding. J. Chem. Soc. Dalton Trans. 1995, 3721-3726.
  8. Barnham K.J., Berners-Price S.J., Frenkiel T.A., Frey U, Sadler P.J. Platination pathways for reactions of cisplatin with GG single-stranded and double-stranded decamer oligonucleotides. Angew. Chem. 1995, 34, 1874-1877.
  9. Appleton T.G., Barnham K.J., Byriel K.A., Hall J.R., Kennard C.H.L., Mathieson M.T., Penman K.G. Reactions of nitroplatinum compounds. 2. Reactions of K2[Pt(NO2)4] and related complexes with aqueous acids (CH3CO2H, HClO4, CF3SO3H, HNO3, and H2SO4): Pathways to Platinum(III) Compounds with acetate bridges. The crystal structure of K2[{Pt(NO2)2(m-CH3CO2)}2].H2O. Inorg. Chem. 1995, 34, 6040-6052.
  10. Barnham K.J., Djuran M.I., Murdoch P-D.S., Ranford J.D., Sadler P.J. Ring-opened adducts of the anticancer drug carboplatinum with sulfur amino acids. Inorg. Chem., 1996, 35(4), 1065-1072.
  11. Berners-Price S.J., Barnham K.J., Frey U., Sadler P.J. Kinetic analysis of the stepwise platination of single- and double-stranded GG oligonucleotides with cisplatin and [PtCl(H2O)(NH3)2]+ Chem. Eur. J. 1996, 2(10), 1283-1291.
  12. Arpallahti, J., Sillanpaa, R., Barnham, K.J., Sadler, P.J. X-Ray crystal structure determination and spectroscopic characterisation of Trans-diamminedihydroxoplatinum (II) dihydrate. Acta Chem. Scand. 1996, 50(2), 181-184.
  13. Barnham K.J., Guo, Z.J., Sadler, P.J. Stabilisation of monofunctional platinum-nucleotide adducts of N-acetyl-L-methionine complexes with guanosine 5´-monophosphate and guanylyl(3´-5´)guanosine. J. Chem. Soc. Dalton Trans. 1996, 2867-2876.
  14. Berners-Price S., Barnham K.J., Corrazza A., Guo Z, Sadler, P.J., Leng M., Locker L. Structural transitions of a GG-platinated DNA duplex induced by pH, temperature and Box A of high-mobility-group protein 1. Eur. J. Biochem. 1997, 243, 782-791.
  15. Barnham, K.J., Dyke, T.R., Kem, W.R., Norton, R.S. Structure of the neurotoxin B-IV from the marine worm Cerebratulus lacteus: _-Helical hairpin stabilised by disulfide bonding. J. Mol. Biol. 1997, 268, 886-902.
  16. Barnham, K.J., Monks, S.A., Hinds, M.G., Azad, A.A., Norton R.S. Solution structure of a polypeptide from the N-terminus of the HIV protein Nef. Biochemistry 1997, 36, 5970-5980.
  17. Barton, S.J., Barnham, K.J., Habtemariam, A., Sue, R.E., Sadler, P.J. pKa values of aqua ligands on platinum(II) anticancer complexes: [1H, 15N] and 195Pt NMR studies of Cis- and Trans-[PtCl2(NH3)(cyclohexylamine)] Inorg. Chim. Acta 1998, 273, 8-13.
  18. Ivanov, A.I., Christodoulou, J., Parkinson, J.A., Barnham, K.J., Tucker, A., Woodrow, J., Sadler, P.J. Cisplatin binding sites on human albumin. J. Biol. Chem. 1998, 273, 14721-14730.
  19. Barnham, K.J., Torres, A.T., Alewood, D., Alewood, P.F., Domagala, T., Nice, E.C., Norton, R.S. Role of the 6-20 disulfide bridge in the structure and activity of epidermal growth factor. Protein Sci. 1998, 7, 1738-1749.
  20. Barton S.J., Barnham K.J., Frey U., Habtemariam A., Sue R.E., Sadler P.J. [1H,15N] NMR kinetic studies of reactions of cis and trans-[PtCl2(15NH3)(c-C6H1115NH2)] with guanosine-5´-monophosphate Aust. J. Chem 1999, 52, 173-177.
  21. Cox M.C., Barnham K.J., Frenkiel T.A., Hoeschele J. D., Mason A.B., He•Q.-Y., Woodworth R.C., Sadler P.J. Identification of platination sites on human serum transferrin using 13C and 15N NMR spectroscopy. J. Bioinorg. Chem. 1999, 4, 621-631.
  22. Barnham, K.J., Catalfamo, F., Pallaghy, P.K., Howlett, G.J., Norton, R.S. Helical structure and self-association in a 13 residue neuropeptide YY2 receptor agonist: Relationship to biological activity. BBA-Protein Struct. 1999, 1435, 127-137.
  23. Cherny, R.A., Barnham, K.J., Lynch, T., Volitakis, I., Li, Q-X., McLean, C.A., Multhaup, G., Beyreuther, K., Tanzi, R.E., Masters, C.L., Bush A.I. Chelation and intercalation: Complimentary properties in a compound for the treatment of Alzheimer's disease. J. Struct. Biol. 2000, 130, 209-216.
  24. Thompson, A.J., Barnham, K.J., Norton, R.S., Barrow, C.J. The Val-210-Ile pathogenic Creutzfeld-Jakob disease mutation increases both the helical and aggregation propensities of a sequence corresponding to helix-3 of PrP. BBA-Protein Struct. 2001, 1544, 242-254.
  25. Jobling, M.F., Huang, X., Stewart, L.R., Barnham, K.J., Curtain, C., Volitakis, I., Perugini, M., White, A.R., Cherny, R., Masters, C.L., Barrow, C.J., Collins, S.J., Bush, A.I., Cappai, R. Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126. Biochemistry 2001, 40, 8073-8084.
  26. Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A., Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y.-S., Goldstein, Huang, X., L.E., Moir, R.D., Lim, J.T., Beyreuther, K.T., Zheng, H., Tanzi, R.E., Masters, C.L., Bush, A.I. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001, 30, 665-676.
  27. Curtain, C.C., Ali, F., Volitakis, I., Cherny, R.A., Norton, R.S., Beyreuther, K., Barrow, C.J., Masters, C.L., Bush, A.I., Barnham. K.J. Alzheimer’s disease amyloid-b binds Cu and Zn to generate an allosterically ordered membrane-penetrating structure containing SOD-like subunits. J. Biol. Chem. 2001, 276, 20466-20473.
  28. Gorman, J.J., McKimm-Breschkin J.L., Norton R.S., Barnham K.J. Antiviral Activity and Structural Characteristics of the Non-Glycosylated Central Subdomain of Human Respiratory Syncytial Virus Attachment (G) Glycoprotein. J.Biol. Chem. 2001, 276, 38988-38994.
  29. Corzo, G., Escoubas, P., Villegas, E., Barnham, K.J., He, W., Norton, R.S., Nakajima, T. Pandinins, novel amphipathic antimicrobial peptides from venom of the scorpion Pandinus imperator. Biochem. J. 2001, 359, 35-45.
  30. Pannequin J, Barnham K.J., Hollande F., Shulkes A., Norton R.S., Baldwin G.S. Ferric ions are essential for the biological activity of the hormone glycine-extended gastrin. J. Biol. Chem. 2002, 277, 48602-48609.
  31. Miles L.A., Dy C.Y., Nielsen J., Barnham K.J., Hinds M.G., Olivera B.M., Bulaj G., Norton R.S. Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif. J. Biol. Chem. 2002, 277, 43033-43040.
  32. Hewish D.R., Barnham K.J., Werkmeister J.A., Kirkpatrick A., Bartone N., Liu S.T., Norton R.S., Curtain C.C., Rivett D.E. Structure and activity of D-Pro(14) melittin. J. Prot. Chem. 2002, 21, 243-253.
  33. Curtain C.C., Ali F.E., Smith D.G., Bush A.I., Masters C.L., Barnham K.J. .Metal ions, pH and cholesterol regulate the interactions of Alzheimer's disease amyloid-b peptide with membrane lipid. J. Biol. Chem. 2003, 278, 2977-2982.
  34. Kourie, J.L. Kenna, B.L. Tew, D. Jobling, M.F. Curtain, C.C. Masters, C.L. Barnham, K.J. Cappai, R. Copper modulation of ion channels of PrP[106-126] mutant prion peptide fragments. J. Membrane Biol. 2003, 193, 35-45.
  35. Barnham, K.J., McKinstry, W.J., Multhaup, G., Galatis, D., Morton, C.J., Curtain, C.C., Williamson, N.A., White, A.R., Hinds, M.G., Norton, R.S., Beyreuther, K., Masters, C.L., Parker, M.W., Cappai, R. Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain: a regulator of neuronal copper homeostasis. J. Biol. Chem. 2003; 278: 17401-17407.
  36. Evin, G., Sernee, M.F, Barnham, K.J., Holsinger, R.M.D, Culvenor, J.G., Hoke, D.E., Li, Q-L., Smith, D.G., Maynard, C., Tickler, A., Huang, X., Opazo, C., Carrington, D., Kocak, G., Volitakis, I., Mok, S.S, Ciccotosto, G, Williamson, N.A., Beyreuther, K., Wade, J., Curtain, C.C., Cherny, R.A., Bush, A.I., Masters, C.L., Cappai, R. Modulation of Alzheimer’s Disease Ab pathways for rational therapeutic intervention: secretase inhibition and metalloprotein active compounds. in Alzheimer’s Disease and Related Disorders: Research Advances. Khalid Iqbal, and Bengt Winblad, Eds. Aslan International Academy of Aging, Bucharest, Romania, 2003
  37. Lau,T-L., Barnham, K.J., Curtain, C.C, Masters, C.L., Separovic, F. Magnetic Resonance Studies of the b-Amyloid Peptide Aust. J. Chem. 2003, 56, 349-356.
  38. Bahadi, R. Farrelly, P.V. Kenna, B.L. Curtain, C.C. Masters, C.L. Cappai, R. Barnham, K.J. Kourie, J.I. Cu2+ -induced modification of the kinetics of Ab1-42 channels. Am. J. Physio-Cell Physio. 2003, 285, C873-C880.
  39. Barnham, K.J., Ciccotosto, G.D., Tickler, A.K., Ali, F.E., Smith, D.G., Williamson, N.A., Lam. Y-H., Carrington D., Tew, D., Kocak, G., Volitakis, I., Separovic, F., Barrow, C.J, Wade, J.D., Masters, C.L., Cherny, R.A., Curtain, C.C., Bush, A.I., Cappai, R. Neurotoxic, redox-competent Alzheimer’s b-amyloid is released from lipid membrane by methionine oxidation. J. Biol. Chem. 2003, 278, 42959-42966.
  40. Tickler, A.K., Barnham, K.J., Wade, J.D. Metal-mediated peptide-lipid interactions of the amyloid-b peptide. In: Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries 2003. R. Epton (ed.), Mayflower Worldwide, England. (in press).
  41. Curtain, C.C., Barnham, K.J., Bush, A.I. Ab Metallobiology and the Development of Novel Metal-Protein Attenuating Compounds (MPACs) for Alzheimer's disease. Curr. Med. Chem. – Imun., Endoc. & Metab. Agents, 2003, 3, 309-315.
  42. Ali, F.E., Barnham, K.J., Barrow, C.J., Separovic, F. Metal Catalyzed Oxidation of Tyrosine Residues by Different Oxidation Systems of Copper/ Hydrogen Peroxide. J. Inorg. Biochem. 2004, 1, 173-188.
  43. Pannequin, J., Kovac, S., Tantiongco, J.-P., Norton, R.S., Shulkes, A., Barnham, K.J., Baldwin, G.S. A novel effect of bismuth Ions: Selective inhibition of the biological activity of glycine-extended gastrin. J. Biol. Chem. 2004, in press
  44. Barnham, K.J., Cherny, R.A., Cappai, R., Melov, S., Masters, C.L., Bush, A.I. Metal-protein attenuating compounds (MPACs) for the treatment of Alzheimer’s disease. Drug Design Reviews-Online, 2004, in press
  45. Yao,S., Cherny,R.A., Bush, A.I., Masters, C.L., Barnham, K.J. Characterizing Bathocuproine Self-association and Subsequent Binding to Alzheimer’s Disease Amyloid-b Peptide by NMR. J. Pept. Sci. 2004, in press.
  46. Barnham, K.J., Masters, C.L., Bush, A.I. Neurodegenerative diseases and oxidative stress. Nature Rev. Drug Disc., 2004, in press

  47. Patents
  48. Cytotoxic Peptides A. Azad, Aruna, K. Barnham, J. Baell, C. Curtain, M. Lowe, I. Macreadie, B. Matthews, R. Norton, D. Rivett (1996) Australia AU97/00640
  49. Beta-Amyloid Peptide Inhibitors K. Barnham, T. McCarthy, S. Pallich, B. Matthews, R. Cherny (1999) Australia AU00/00886K
  50. Method of Screening for Inhibitors of Alzheimer’s disease K. Barnham, R. Cappai, M. Parker, (2000) Australia AU01/01603.
  51. 8-hydroxy quinoline derivativesAU03/00914 K. Barnham, E. Gautier, G. Kok, G. Krippner
  52. "Method of treatment" Baldwin, GS, Shulkes, A, Barnham, KJ, Norton, RS, Pannequin, J, Kovac, S, Tantiongco, JP, He, H. US provisional No: 60/461083