Peter J. Tonge

Chemical Biology, Quantitative PHarmacology, Enzymology, and spectroscopy

Research in the Tonge laboratory is focused on two major areas that explore the role of time in biology: (i) the mechanism of drug action, and (ii) photoreceptor biophysics and biology. In both, we ask how events on one timescale govern outcomes on a much longer one. We design and synthesize inhibitors and degraders of enzyme drug targets involved in diseases such as cancer and infection, and use biochemical and cellular assays coupled with pharmacokinetic/pharmacodynamic (PK/PD) modeling 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, work that has led to optogenetic tools for controlling the rate of protein synthesis in living cells.

Inhibitor and pROTac Discovery: 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 and that the failure to account for binding kinetics may contribute to the high rate of attrition in clinical trials. 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 that provide direct insight into target vulnerability. In our antibacterial program we are particularly interested in compounds that continue to act after the drug has been eliminated from the body – the post-antibiotic effect – since such compounds should permit less frequent dosing with corresponding gains in safety. Drug targets include kinases involved in oncology and inflammation, and enzymes from pathogenic bacteria such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). This project has recently expanded to include the design, synthesis and mechanistic analysis of bivalent PROteolysis TArgeting Chimeras (PROTACs), which catalyze the degradation of drug targets. We compare and contrast the mechanism of these compounds, which cause event-driven pharmacology, with the mechanism of drug-target inhibitors, which result in occupancy-driven pharmacology. 

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 FAD (BLUF) and Light-Oxygen-Voltage (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. Recent studies involve the design of a novel optogenetic tool that controls the rate of protein synthesis in response to light, and that is being used to determine the role of protein translation in learning and memory.

Google Scholar Publications

1. Srinivasan, B., Corrionero, A., Barone, M., Alfonso, P., Prendiville, N., Cazorla, T., Rahiyanath, A. S., Whitty, A., and Tonge, P. (2026) Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand, bioRxiv PMC13228517.
2. Fatima, A., He, Y., Rosenberger, D., Greetham, G. M., Malakar, P., Lukacs, A., Tonge, P. J., and Meech, S. R. (2026) Dynamics and Mechanism of Off- to On-Switching in Dreiklang a Decoupled Reversibly Switchable Fluorescent Protein, Angew Chem Int Ed Engl65, e18264 PMC12707319.
3. Ali, M. I., and Tonge, P. J. (2026) Only time will tell: Modelling the kinetics of covalent inhibitors, Br J Pharmacol PMC13234915.
4. Wang, M., He, Y., Cohen, S. A., Strohm, A. R., Shetye, G., Franzblau, S. G., Walker, S. G., Alley, M. R. K., and Tonge, P. J. (2025) Selectivity of the Time-Dependent M. tuberculosis LeuRS Inhibitor Ganfeborole Is Driven by Target Vulnerability, ACS Chem Biol20, 2955-2965.
5. Rothweiler, E. M., Michaud, A., Stefaniak, J., Singh, U., Mikulsky, B. B., Vasta, J. D., Beck, M. T., Wilkinson, J., Ward, J. A., Rogers, C. M., Balikci, E., Tranberg-Jensen, J., Hansen, J. S., Loppnau, P., Whitty, A., Brennan, P. E., Tonge, P. J., Robers, M. B., and Huber, K. V. M. (2025) A BRET biosensor for measuring uncompetitive engagement of PRMT5 complexes in cells, Nat Commun16, 10129 PMC12675575.
6. He, Y., Gil, A. A., Laptenok, S. P., Fatima, A., Collado, J. T., Iuliano, J. N., Woroniecka, H. A., Brust, R., Sabbah, A., Towrie, M., Greetham, G. M., Sazanovich, I. V., French, J. B., Lukacs, A., Meech, S. R., and Tonge, P. J. (2025) Enhancing Proton-Coupled Electron Transfer in Blue Light Using FAD Photoreceptor AppA(BLUF), J Am Chem Soc147, 39-44 PMC11726546.
7. Gilberti, A. L., Tu, M. M., Rachwalski, K., Ali, M. I., Cohen, S. A., Akoglu, M., Pollard-Kerning, A. C., Tolentino Collado, J., Sabbah, A., Abou Said, F., Dela, P., Walker, S. G., Haley, J. D., Brown, E. D., and Tonge, P. J. (2025) Identifying Modulators of the Post-Antibiotic Effect, ACS Infect Dis11, 2542-2552.
8. Corrionero, A., Zhang, X., Alfonso, P., Morris, P. J., Klumpp-Thomas, C., Melani, C., McKnight, C., Phelan, J. D., Holland, D., Wilson, K., Hoyt, S. B., Roschewski, M., Tonge, P. J., Wilson, W., Ceribelli, M., Staudt, L. M., and Thomas, C. J. (2025) An Assessment of Kinase Selectivity, Enzyme Inhibition Kinetics and in Vitro Activity for Several Bruton Tyrosine Kinase (BTK) Inhibitors, ACS Pharmacol Transl Sci8, 4312-4325 PMC12707263.
9. Bravo, E., Jr., Li, Y., Lin, D. Y., Srinivasan, B., Barone, M., Li, S. X., DelloRusso, F., Rahiyanath, A. S., Corrionero, A., Alfonso, P., Prendiville, N., Kozakov, D., Andreotti, A. H., and Tonge, P. J. (2025) Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects, J Am Chem Soc147, 27876-27891.
10. Li, Y. Q., Lannigan, W. G., Davoodi, S., Daryaee, F., Corrionero, A., Alfonso, P., Rodriguez-Santamaria, J. A., Wang, N., Haley, J. D., and Tonge, P. J. (2023) Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy, J Med Chem66, 7454-7474 PMC10332445.
11. Cifone, M. T., He, Y., Basu, R., Wang, N., Davoodi, S., Spagnuolo, L. A., Si, Y., Daryaee, T., Stivala, C. E., Walker, S. G., and Tonge, P. J. (2022) Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity, J Med Chem65, 16510-16525 PMC10303036.
12. Basak, S., Li, Y., Tao, S., Daryaee, F., Merino, J., Gu, C., Delker, S. L., Phan, J. N., Edwards, T. E., Walker, S. G., and Tonge, P. J. (2022) Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors, J Med Chem65, 11854-11875.

Alfred P. Sloan Research Fellowship, 2001
PhRMA Foundation Sabbatical Fellowship at Genentech, 2017

Director, Center for Advanced Study of Drug Action
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
Founder and Owner, Chronus Pharmaceuticals Inc. 

Member of the Stony Brook Cancer Center