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

B. J. Wylie, C. D. Schwieters, E. Oldfield, C. M. Rienstra. Protein Structure Refinement Using 13C# Chemical Shift Tensors. JACS, online

I. Rekittke, J. Wiesner, R. Rohrich, U. Demmer, E. Warkentin, W. Xu, K. Troschke, M. Hintz, J. H. No, E. C. Duin, E. Oldfield, H. Jomaa, U. Ermler. Structure of (E)-4-Hydroxy-3-methyl-but-2-enyl Diphosphate Reductase, the Terminal Enzyme of the Non-Mevalonate Pathway.

D. Mukkamala, J. H. No, L. M. Cass, T. K. Chang, E. Oldfield. Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme Data. J. Med. Chem., 51, 7827-7833, (2008).

G. Sarikonda, H. Wang, K. J. Puan, X. h. Liu, H. K. Lee, Y. Song, M. D. Distefano, E. Oldfield, G. D. Prestwich, C. T. Morita. Photoaffinity Antigens for Human gammadelta T Cells. J. Immunol., 171, 7738-7750, (2008).

C. K-M Chen, M.P. Hudock, Y. Zhang, R.T. Guo, R. Cao, J.H. No, P.H. Liang, T.P. Ko, T.H. Chang, S.C. Chang, Y. Song, J. Axelson, A. Kumar, A.H. Wang, E. Oldfield. Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem., 51, 5594-607, (2008).

Y. Song,J.M. Chan, Z. Tovian, A. Secrest, E. Nagy, K. Krysiak, K. Bergan, M.A. Parniak, E. Oldfield. Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: A QSAR investigation. Bioorg Med Chem., 16, 8959-8967, (2008).

P.K. Babu, J.-H. Chung, E. Oldfield, A. Wieckowski CO surface diffusion on platinum fuel cell catalysts by electrochemical NMR Elecrochimica Acta, 53, 6672-6679, (2008).

Y. Zhang, E. Oldfield. NMR Hyperfine Shifts in Blue Copper Proteins: A Quantum Chemical Investigation. J. Am. Chem. Soc., 130, 3814-3823, (2008).

Cao R, Chen CK, Guo RT, Wang AH, Oldfield E. Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases. Proteins, 73, 431-9, (2008).

C. Liu, G. Y. Liu, Y. Song, F. Yin, M. E. Hensler, W.-Y. Jeng, V. Nizet, A. H.-J. Wang, E. Oldfield. A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence Science, 319, 1391-1394, (2008).

S. Mukherjee, Y. Song, and E. Oldfield. NMR Investigations of the Static and Dynamic Structures of Bisphosphonates on Human Bone: a Molecular Model J. Am. Chem. Soc., 130, 1264-1273, (2008).

P. K. Babu, A. Lewera, J.-H. Chung, R. Hunger, W. Jaegermann, N. Alonso-Vante, A. Wieckowski, E. Oldfield. Selenium Becomes Metallic on Ru/Se Fuel Cell Catalysts: An EC-NMR and XPS Investigation J. Am. Chem. Soc., 129, 15140-15141, (2007).

Y. Zhang, M.P. Hudock, K. Krysiak, R. Cao, K. Bergan, F. Yin, A. Leon and E. Oldfield. Activity of Sulfonium Bisphosphonates on Tumor Cell Lines J. Med. Chem., 50, 6067-6079, (2007).

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. Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases: a crystallographic investigation Proc. Natl. Acad. Sci. USA, 104, 10022-10027 (2007).

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

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

Takeshi Kobayashi, Panakkattu K Babu, Jong Ho Chung, Eric Oldfield and Andrzej Wieckowski. Coverage dependence of CO surface diffusion on Pt nanoparticles: an EC-NMR investigation. J. Phys. Chem. C, 111, 7078-7083, (2007)

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

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)
• Fellow of the American Association for the Advancement of Science (2008)
• Soft Matter and Biophysical Award from the Royal Society of Chemistry (2009)

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.