Eric Oldfield

Research

In recent work, carried out in collaboration with the groups of J. Urbina, R. Docampo and S. Croft, we have branched out into yet another new area, molecular parasitology. We first found evidence for extremely large levels of inorganic di- and triphosphate in the protozoa which cause African sleeping sickness and malaria. This then led us to the idea that it might be possible to kill these and other related parasites by using stable diphosphate analog drugs to block specific metabolic pathways, and this indeed was found to be the case. The drugs used, called bisphosphonates, have been used to treat bone-resorption diseases for over 20 years, but their mode of action had been unknown. However, in recent work, we have shown that the most potent, nitrogen-containing bisphosphonates used in treating bone diseases are also potent drugs in killing parasites, and act to perturb protein prenylation and signaling by inhibiting the enzyme farnesyl pyrophosphate synthase. Using quantum chemistry and molecular modeling, we showed that the charged ammonium side-chains in the drugs act as carbocation transition state analogs, and bind into the active site of the enzyme, blocking its action. This gives a sound molecular basis for drug design, based on known protein structures and mechanisms of drug action, and is a topic of considerable current interest.

And finally, in our most recent work we have found that it is possible to apply the computational methods used in modern drug design and drug discovery to the immune system where we are employing QSAR (quantitative structure activity relationships) to probe innate immunity. In particular, we are interested in the development of drugs which activate γδ T cells, opening the way to new therapies for infectious diseases, cancer, and vaccine development.

Publications

Y. Zhang, Y. Song, F. Yin, E. Broderick, K. Siegel, A. Goddard, E. Nieves, L. Pasa-Tolic, Y. Tanaka, H. Wang, C.T. Morita, E. Oldfield, Chem. Biol., 13, 985-992 (2006), Structural studies of Vγ2Vδ2 T cell phosphoantigens

S. B. Gabelli, J. S. McLellan, A. Montalvetti, E. Oldfield, R. Docampo and L. M. Amzel, Proteins, 62, 80-88 (2006), Structure and mechanism of the farnesyl pyrophosphate synthase from Trypanosoma cruzi: implications for drug design

G. Benaim, Y. Garcia-Marchan, C. Colina, R. Lira, A. R. Caldera, G. Payares, C. Sanoja, J. M. Burgos, J. M. Sanders, A. Leon-Rossell, J. L. Concepcion, A. Schijman, M. Levin and E. Oldfield and J. Urbina, J. Med. Chem., 49, 892-8999 (2006). Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.

Y. Zhang and E. Oldfield, J. Am. Chem. Soc., J. Phys. Chem. B., 110, 579-86 (2006), 31P NMR chemical shifts in hypervalent oxyphosphoranes and polymeric orthophosphates.

M.P. Hudock, C.E. Sanz-Rodriguez, Y. Song, J. Chan, Y. Zhang, S. Odeh, T. Kosztowski, A. Leon-Rossell, J.L. Concepcion, V. Yardley, S.L. Croft, J.A. Urbina and E. Oldfield. J. Med. Chem., 49, 215-223 (2006). Inhibition of Trypanosoma Cruzi Hexokinase by Bisphosphonates.

A. Leon, L. Liu, Y. Yang, M.P. Hudock, P. Hall, F. Yin, D. Studer, K.-J. Puan, C.T. Morita and E. Oldfield, J. Med. Chem., 49, 7331-7341 (2006)., Isoprenoid biosynthesis as a drug target: Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin

H. Imai, P. K. Babu, E. Oldfield, A. Wieckowski, D. Kasuya, T. Azami, Y. Shimakawa, M. Yudasaka, Y. Kubo and S. Iijima, Phys. Rev. B, 73, 125405-1-7 (2006). A 13C NMR spectroscopic investigation of carbon nanohorns.

Y. Zhang, J. C. Lewis, R. G. Bergman, J. A. Ellman and E. Oldfield, Organometallics, 25, 3515-3519. NMR shifts, orbitals, and M…H-X bonding in d8 square planar metal complexes.

J. Mao, S. Mukherjee, Y. Zhang, R. Cao, J. M. Sanders, Y. Song, Y. Zhang, G. A. Meints, Y. G. Gao, D. Mukkamala, M.P. Hudock, J. Am. Chem. Soc., 128, 14485-14497 (2006), A solid state NMR, crystallographic and quantum chemical investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes

Y. Ling, G. Sahota, S. Odeh, J.M. Chan, F.G. Araujo, S.N. Moreno, E. Oldfield, J. Med. Chem., 48, 3130-3140, Bisphosphonate inhibitors of Toxoplasma gondi growth: in vitro, QSAR, and in vivo investigations

F. Yin, R. Cao, A. Goddard, Y. Zhang and E. Oldfield, J. Am. Chem. Soc., 128, 3524-5 (2006). Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase.

R. Cao, M. P. Hudock, Y. Zhang, S. R. Wilson and E. Oldfield, Acta Cryst., Sec. E., 62, o1003-o1006. [2-(3-Fluoropyridinium-1-yl)-1-hydroxy-1-phosphonoethyl]phosphonate.

M. P. Hudock, R. Cao, Y. Zhang, S. R. Wilson and E. Oldfield, Acta Cryst., Sec. E., 62, o843-o845. 1-Hydroxy-1-phosphono-2-(trimethylarsonium-1-yl)ethanephosphonate mono hydrate.

R. Cao, M. P.Hudock, Y. Zhang, S. R. Wilson, Acta Cryst., Sec. E., 62, o1055-o1057. 1-Hydroxy-2-(trimethylphosphonium-1-yl)ethylidene 1,1-bisphosphonate.

Y. Zhang, R. Cao, M. P. Hudock, S. R. Wilson and E. Oldfield, Acta Cryst., Sec. E., 62, o1006-o1008. [2-(Dimethylsulfonio)-1-hydroxy-1-phosphonoethyl]phosphonate monohydrate.E. Kotsikorou, G. Sahota and E. Oldfield, J. Med. Chem., 49, 6692-703 (2006), Bisphosphonate inhibition of phosphoglycerate kinase: A quantitative structure activity relationship and pharmacophore modeling investigation

G. Kervern, G. Pintacuda, Y. Zhang, E. Oldfield, C. Roukoss, E. Kuntz, E. Herdtweck, J.-M. Baseet, S. Cadars, A. Lesage, C. Coperet and L. Emsley, J. Am. Chem. Soc., 128, 13545-52 (2006), Solid-state NMR of a paramagnetic DIAD-FeII catalyst: sensitivity, resolution enhancement, and structure-based assignments.

C.E. Sanz-Rodriguez, J.L. Conception, S. Pekerar, E. Oldfield and J.A. Urbina, J. Biol. Chem., 282, 12377-87 (2007), Bisphosphonates as allosteric inhibitors of Trypanosoma cruzi hexokinase: Kinetic and metabolic studies

Takeshi Kobayashi, Panakkattu K Babu, Jong Ho Chung, Eric Oldfield and Andrzej Wieckowski, J. Phys. Chem. C, online, Coverage dependence of CO surface diffusion on Pt nanoparticles: an EC-NMR investigation.

H. Yano, J. Inukai, H. Uchida, M. Watanabe, P.K. Babu, T. Kobayashi, J.H. Chung, E. Oldfield, A. Wieckowski, Phys. Chem. Chem. Phys., 8, 4932-4939 (2006), Particle-size effect in a platinum nanoscale catalyst on the oxygen reduction reaction: An electrochemical and 195Pt EC-NMR study.

D. Mukkamala, Y. Zhang and E. Oldfield, J. Am. Chem. Soc., 129, 7385-7392 (2007), A Solid State 13C NMR, Crystallographic and Quantum Chemical Investigation of Phenylalanine and Tyrosine Residues in Dipeptides and Proteins

R.-T. Guo, R. Cao, T.-H. Chang, T.-P. Ko, W.-Y. Jeng, C. K.-M. Chen, M. P. Hudock, Y. Zhang, Y. Song, P.-H. Liang, E. Oldfield and A. H.-J. Wang, Proc. Natl. Acad. Sci. USA, 104, 10022-10027 (2007)., Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases: a crystallographic investigation

Awards

• Thomas Malkin Prize (1968)
• William Edward Garner Prize (1969)
• European Molecular Biology Organization Fellowship (1972-1974)
• The Meldola Medal and Prize of The Royal Institute of Chemistry (1977)
• Alfred P. Sloan Research Fellowship (1978-1980)
U.S. Public Health Service Research Career Development Award (1979-1984)
• American Heart Association Louis N. Katz Basic Science Research Prize (1980)
• Fellow of the Royal Society of Chemistry (1981)
• Fellow, American Institute of Chemists (1982)
• The Colworth Medal of the Biochemical Society (1983)
• American Chemical Society Award in Pure Chemistry (1984)
• Fellow, American Physical Society (1993)
• Richard G. and Carole J. Cline University Senior Scholar (1995)
• Royal Society of Chemistry Award in Spectroscopy (1995)
• Associate, Center for Advanced Study (2000-2001)
• Alumni Research Scholar Professor of Chemistry (2002-2007)
• Campus Award for Excellence in Guiding Undergraduate Research (2006)

Highlights

"Antimicrobials: Cholesterol-biosynthesis inhibitor stops infection" by Sarah Crunkhorn. Read the Nature Reviews Drug Discovery article here.

"Lowering Cholesterol Good for Us, Bad for Bacteria": Read the Naked Scientists article about Dr. Oldfield's research here.

"Novel Approach Strips Staph of Virulence": Read the National Institute of General Medical Sciences article about Dr. Oldfield's research here.