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Faculty


Peter J. Tonge

Peter J. Tonge, Professor
PROFESSOR, DEPARTMENT OF RADIOLOGY (by courtesy)

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
633 Chemistry
Phone: (631) 632-7907 | Lab: (631) 632-5797 | Fax: (631) 632-7934
Email: peter.tonge@stonybrook.edu

LinkedIn Profile
The Tonge Group Website
Publications

AWARDS

Alfred P. Sloan Research Fellowship, 2001
PhRMA Foundation Fellowship, 2017

Positions

Co-Director, Chemical Biology Training Program
Director, Biomolecular Imaging Cluster
Director, Infectious Disease Research, Institute for Chemical Biology and Drug Discovery
Director, Translational Experimental Therapeutics Laboratory, Stony Brook University School of Medicine
Member of the Graduate Programs in Biochemistry & Structural Biology, Molecular & Cellular Biology, Molecular Genetics and Microbiology, Molecular & Cellular Pharmacology
Member of the Center for Infectious Diseases

Chemical Biology, Enzymology and Spectroscopy

Research in the Tonge laboratory focuses on two major areas: (i) inhibitor discovery and the mechanism of drug action, and (ii) photoreceptor biophysics and biology. We design and synthesize inhibitors of enzyme drug targets involved in infectious diseases, cancer, and inflammation and use PK/PD models coupled with 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 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 drug 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. We are also actively focused on targets from oncology and inflammation such as tyrosine kinases.

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 and LOV 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.

Selected Publications

  1. Li HJ, Lai CT, Pan P, Yu W, Liu N, Bommineni GR, Garcia-Diaz M, Simmerling C, Tonge PJ. A structural and energetic model for the slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA. ACS Chem Biol 2014, 9, 986-93. PMC4004265 Medline
  2. Walkup GK, You Z, Ross PL, Allen EK, Daryaee F, Hale MR, O'Donnell J, Ehmann DE, Schuck VJ, Buurman ET, Choy AL, Hajec L, Murphy-Benenato K, Marone V, Patey SA, Grosser LA, Johnstone M, Walker SG, Tonge PJ, Fisher SL. Translating slow-binding inhibition kinetics into cellular and in vivo effects. Nat Chem Biol 2015, 11, 416-23. PMC4536915 Medline
  3. Gil AA, Haigney A, Laptenok SP, Brust R, Lukacs A, Iuliano JN, Jeng J, Melief EH, Zhao RK, Yoon E, Clark IP, Towrie M, Greetham GM, Ng A, Truglio JJ, French JB, Meech SR, Tonge PJ. Mechanism of the AppABLUF Photocycle Probed by Site-Specific Incorporation of Fluorotyrosine Residues: Effect of the Y21 pKa on the Forward and Reverse Ground-State Reactions. J Am Chem Soc 2016, 138, 926-35.PMC4830125Medline
  4. Matarlo JS, Lu Y, Daryaee F, Daryaee T, Ruzsicska BP, Walker SG, Tonge PJ. A Methyl 4-Oxo-4-phenylbut-2-enoate with in Vivo Activity against MRSA that Inhibits MenB in the Bacterial Menaquinone Biosynthesis Pathway. ACS Infect Dis 2016, 2, 329-340.PMC4898059 Medline
  5. Daryaee F, Chang A, Schiebel J, Lu Y, Zhang Z, Kapilashrami K, Walker SG, Kisker C, Sotriffer CA, Fisher SL, Tonge P J. Correlating Drug-Target Kinetics and In vivo Pharmacodynamics: Long Residence Time Inhibitors of the FabI Enoyl-ACP Reductase. Chem Sci 2016 7, 5945-5954.PMC4988406 Medline
  6. Spagnuolo LA, Eltschkner S, Yu W, Daryaee F, Davoodi S, Knudson SE, Allen EK, Merino J, Pschibul A, Moree B, Thivalapill N, Truglio JJ, Salafsky J, Slayden RA, Kisker C, Tonge PJ. Evaluating the contribution of transition state destabilization to changes in the residence time of triazole-based InhA inhibitors. J Am Chem Soc  2017.Medline
  7. Zhang Z, Ordonez AA, Smith-Jones P, Wang H, Gogarty KR, Daryaee F, Bambarger LE, Chang YS, Jain SK, Tonge PJ. The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography. PLoS One  2017, 12, e0170871. PMC5289470Medline
  8. Gil AA, Laptenok SP, French JB, Iuliano JN, Lukacs A, Hall CR, Sazanovich IV, Greetham GM, Bacher A, Illarionov B, Fischer M, Tonge PJ, Meech SR. Femtosecond to Millisecond Dynamics of Light Induced Allostery in the Avena sativa LOV Domain. J Phys Chem B  2017, 121, 1010-1019. Medline
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