Peter J. Tonge

Chemical Biology, PHarmacology, spectroscopy and PET Imaging

Research in the Tonge laboratory is focused on three major areas that explore the role of Time in biology: (i) the mechanism of drug action, (ii) photoreceptor biophysics and biology, and (iii) PET imaging. We design and synthesize inhibitors of enzyme drug targets involved in diseases such as cancer and infection, and use techniques such as pharmacokinetic/pharmacodynamic (PK/PD) modeling, mass spectrometry and positron emission tomography (PET) to explore the role of drug-target binding kinetics in drug activity at the cellular and whole organism level. We also synthesize PROteolysis TArgeting Chimeras (PROTACs) which catalyze the degradation of drug targets. 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. In addition to exploring the role of drug action using PET imaging, we also develop radiotracers to detect and localize bacterial infection in humans.

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. 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 provides direct insight into target vulnerability and is aided by the development of drug positron emission tomography (PET) radiotracers to quantify target occupancy in vivo. Drug targets include kinases involved in oncology and inflammation, and enzymes from pathogenic bacteria. 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 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.

PET Imaging Diagnostics for Deep Seated Infections

Bacterial infections such as those of prosthetic joints, bones (osteomyelitis) and heart valves (infective endocarditis) are difficult to difficult to diagnose and treat, and are a major cause of mortality, morbidity and health care costs. We are developing positron emission tomography (PET) radiotracers that can be used for non-invasive PET imaging to detect and localize bacterial pathogens in humans. Such radiotracers will distinguish between different pathogen populations, serve as non-invasive diagnostics, and inform on bacterial load during chemotherapy, thereby identifying and improving treatment of patients with infectious diseases.

Google Scholar Publications

1. Li HJ, Lai CT, Pan P, Yu W, Liu N, Bommineni GR, Garcia-Diaz M, Simmerling C, and Tonge PJ. (2014) ACS Chem Biol 9, 986-993. A structural and energetic model for the slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA. DOI: 10.1021/cb400896g.
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, and Fisher SL. (2015) Nat Chem Biol 11, 416-423. Translating slow-binding inhibition kinetics into cellular and in vivo effects. DOI: 10.1038/nchembio.1796.
3. Daryaee F, Zhang Z, Gogarty KR, Li Y, Merino J, Fisher SL, and Tonge PJ. (2017)Chem Sci 8, 3434-3443. A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy.DOI: 10.1039/c6sc03306g
4. 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, and Tonge PJ. (2017) J Am Chem Soc 139,  3417-3429. Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors. DOI: 10.1021/jacs.6b11148.
5. Gil AA, Laptenok SP, Iuliano JN, Lukacs A, Verma A, Hall CR, Yoon GE, Brust R, Greetham GM, Towrie M, French JB, Meech SR*, and Tonge PJ*. (2017) J Am Chem Soc1 39, 14638-14648. Photoactivation of the BLUF Protein PixD Probed by the Site-Specific Incorporation of Fluorotyrosine Residues. DOI: 10.1021/jacs.7b07849.
6. Laptenok SP, Gil AA, Hall CR, Lukacs A, Iuliano JN, Jones GA, Greetham GM, Donaldson P, Miyawaki A, Tonge PJ*, and Meech SR*. (2018) Nat Chem 10,  845-852. Infrared spectroscopy reveals multi-step multi-timescale photoactivation in the photoconvertible protein archetype dronpa. DOI: 10.1038/s41557-018-0073-0.
7. Tonge PJ. (2018) ACS Chem Neurosci 9, 29-39. Drug-Target Kinetics in Drug Discovery.DOI: 10.1021/acschemneuro.7b00185.
8. Hall CR, Tolentino Collado J, Iuliano JN, Gil AA, Adamczyk K, Lukacs A, Greetham GM, Sazanovich I, Tonge PJ, and Meech SR. (2019) J Phys Chem B123, 9592-9597. Site-Specific Protein Dynamics Probed by Ultrafast Infrared Spectroscopy of a Noncanonical Amino Acid. DOI: 10.1021/acs.jpcb.9b09425.
9. Davoodi S, Daryaee F, Chang A, Walker SG, and Tonge PJ. (2020) ACS Infect Dis6, 629-636. Correlating Drug-Target Residence Time and Post-antibiotic Effect: Insight into Target Vulnerability. DOI: 10.1021/acsinfecdis.9b00484.
10. Li Y, Daryaee F, Yoon GE, Noh D, Smith-Jones PM, Si Y, Walker SG, Turkman N, Meimetis L, and Tonge PJ. (2020) ACS Infect Dis6, 2249-2259. Positron Emission Tomography Imaging of Staphylococcus aureus Infection Using a Nitro-Prodrug Analogue of 2-[(18)F]F-p-Aminobenzoic Acid. DOI: 10.1021/acsinfecdis.0c00374.
11. Iuliano JN, Collado JT, Gil AA, Ravindran PT, Lukacs A, Shin S, Woroniecka HA, Adamczyk K, Aramini JM, Edupuganti UR, Hall CR, Greetham GM, Sazanovich IV, Clark IP, Daryaee T, Toettcher JE, French JB, Gardner KH, Simmerling CL, Meech SR, and Tonge PJ. (2020) ACS Chem Biol15, 2752-2765. Unraveling the Mechanism of a LOV Domain Optogenetic Sensor: A Glutamine Lever Induces Unfolding of the Jalpha Helix. DOI: 10.1021/acschembio.0c00543.
12. Basu R, Wang N, Basak S, Daryaee F, Babar M, Allen EK, Walker SG, Haley JD, and Tonge PJ. (2021) ACS Infect Dis. Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity. DOI: 10.1021/acsinfecdis.1c00317.

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

Director, Center for Advanced Study of Drug Action
Co-Director, Chemical Biology Training Program
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.