Tonge, Peter J. - Stony Brook University

个人简介

B.Sc., 1982, University of Birmingham, England Ph.D., 1986, University of Birmingham, England SERC-NATO Postdoctoral Research Fellowship, National Research Council Canada, 1986-1988 Alfred P. Sloan Research Fellowship, 2001

研究领域

Chemical Biology, Enzymology and Spectroscopy The Tonge Group has two general areas of interest: (i) inhibitor discovery and the mechanism of drug action, and (ii) photoreceptor biophysics and biology. We use mechanistic enzymology to develop inhibitors of enzyme drug targets from pathogens such as Mycobacterium tuberculosis, Burkholderia pseudomallei and methicillin-resistant Staphylococcus aureus (MRSA), and use techniques such as mass spectrometry and positron emission tomography to explore the role of drug-target binding kinetics in drug activity at the cellular and whole organism level. We also use biophysical methods such as ultrafast vibrational spectroscopy coupled with site-specific protein modification to understand the mechanism of photoreceptor activation as a prelude to the development of optogenetic devices. Inhibitor Discovery and the Mechanism of Drug Action We use mechanistic information to design and synthesize high affinity enzyme inhibitors that have long residence times on their targets based on the knowledge that drug-target residence time is a critical factor for in vivo antibacterial activity. The long residence time inhibitors are being used to explore how kinetic selectivity influences the therapeutic index of drugs and to drive the development of mechanistic pharmacokinetic-pharmacodynamic PK-PD models. The PK-PD modeling is aided by drug biodistribution provided by positron emission tomography and so one active area involves the development of radiotracers that incorporate carbon-11 and fluorine-18. Many of the drug targets we study are from pathogenic bacteria and include enzymes from the fatty acid biosynthesis and menaquinone biosynthesis pathways as well as those involved in transcription and translation. Photoreceptor Biophysics and Biology Photoreceptors are proteins that have evolved specifically to convert light energy into structural change, and thus serve as prototypes for light driven molecular and biomolecular devices. We are using vibrational spectroscopy coupled with unnatural amino acid mutagenesis to determine how photoexcitation on the ultrafast timescale leads to structural changes on the biologically relevant µs-ms time scales. Currently our focus is on the Blue Light Using Flavin adenine dinucleotide (BLUF) domain photoreceptors which are of central importance in the emerging technology of optogenetics where light is used to control specific cellular responses using genetically encoded sensors.

近期论文

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Brust R, Lukacs A, Haigney A, Addison K, Gil A, Towrie M, Clark IP, Greetham GM, Tonge PJ, Meech SR. (2013) J Am Chem Soc. 135, 16168–16174. Proteins in Action: Femtosecond to Millisecond Structural Dynamics of a Photoactive Flavoprotein. Medline Chang A, Schiebel J, Yu W, Bommineni GR, Pan P, Baxter MV, Khanna A, Sotriffer CA, Kisker C, Tonge PJ. (2013) Biochemistry, 52, 4217-28. Rational Optimization of Drug-Target Residence Time: Insights from Inhibitor Binding to the Staphylococcus aureus FabI Enzyme-Product Complex. Medline E.A. Weinstein ,E.A., Liu, L., Ordonez, A.A., Wang, H., Hooker, J.M., Tonge, P.J. and Jain, S.K. (2012) Antimicrob. Agents Chemother. 56(12):6284-90. Noninvasive Determination of 2-[18F]-Fluoroisonicotinicacid hydrazide Pharmacokinetics by Positron Emission Tomography in Mycobacterium tuberculosis Infected Mice. Medline Lu, H. and Tonge, P.J. (2010) Curr. Opin. Chem. Biol. 14, 467-474. Drug-target residence time: critical information for lead optimization. Medline