Using Innovative Methods to Predict and Improve the Efficacy of Drugs

Understanding how drugs work will lead to improved therapies for all areas of disease

The current drug discovery process is extremely inefficient: more than 90% of drug candidates fail in human clinical trials. Dr. Peter Tonge, Professor of Chemistry at Stony Brook University, is developing novel methods to improve the prediction of drug activity in the human body and to design safer, better drugs. Current approaches largely ignore the rate at which drugs bind to and dissociate from their targets. By designing innovative mathematical models that use drug-target kinetics Dr. Tonge seeks to improve the science of drug discovery and our ability to predict how well drugs will work. This has important implications for improving drugs in all therapeutic areas of disease. He also develops bacteria-specific imaging agents to quantify drug efficacy.

The primary reason drugs fail in clinical trials is because the “therapeutic window” is not large enough. Too little drug can be ineffective, but too much drug may result in unwanted side effects. Dr. Tonge wants to improve the science of drug discovery by fundamentally understanding how drugs work in humans; where they go, what they bind to, and how long they stay there. To make better, safer drugs, Dr. Tonge is developing compounds that dissociate slowly from their targets; such compounds will have extended activity at low drug concentration, thus reducing the frequency of dosing and improving safety. To do this, Dr. Tonge measures both the thermodynamics and kinetics of drug target interactions (i.e. the rates at which drugs bind to and dissociate from their targets), and uses mathematical models to predict the amount of drug needed to cause the desired effect. Current drug discovery programs typically rely on thermodynamic parameters alone, largely ignoring the kinetics of drug-target interactions. Although thermodynamics determine whether or not a reaction occurs, thermodynamic parameters do not inform on how long it takes for the reaction to happen. Dr. Tonge couples both thermodynamic and kinetic approaches in his novel mathematical models to quantify time-dependent changes in target occupancy and hence predict how long a drug will work.

Dr. Tonge and his interdisciplinary team of graduate students collaborate extensively with experts from around the world. Combining their diverse approaches, they use innovative techniques that include organic synthesis, medicinal chemistry, enzymology, microbiology, animal models of disease, NMR spectroscopy, X-ray crystallography, time-resolved vibrational spectroscopy, non-invasive positron emission tomography (PET) imaging and mathematical (PK/PD) modeling. Though their technology is applicable across all disease sectors, they’re currently focused on antibiotic and oncology/inflammation targets. They aim to develop molecules that are more successful than current compounds, moving them into human clinical trials within two to three years.

Current research includes:

  • Developing Kinetic Models to Predict Drug Activity - When drugs stick to their target for a long time, they continue working, even if the drug concentration is low. This allows the drug dosage to be decreased, which can improve patient compliance (after all, it’s easier to take one pill a day than four), reduce negative side effects, and prevent the emergence of drug resistance. By using novel drug-target kinetics, Dr. Tonge and his team are developing antibacterial compounds that dissociate slowly from their targets. They are looking at high-risk Gram-positive and Gram-negative bacteria, which cause life-threatening diseases—particularly in patients that are hospitalized—and neglected diseases such as those caused by Mycobcaterium tuberculosis. Using their novel kinetic approach, they seek to understand why drugs remain bound to their target for different periods of time, and to design drugs with optimized dissociation rates and improved therapeutic windows.
  • Identifying Novel PET Radiotracers - Most hospitals use non-invasive PET scanners to image tumors. Radiotracers are taken up by a tumor and detected by a PET camera that surrounds the patient, enabling doctors to look at the size of the tumor and how it responds to chemotherapy. Though PET has had a profound impact on imaging disease and probing brain function, there is no radiotracer that directly images bacterial infection. Because of their location in the body, bacterial infections can often only be detected through biopsies. Dr. Tonge and his team are developing novel bacteria-specific radiotracers that can be used to detect and localize bacterial infections in humans using PET. The development of a PET radiotracer that can selectively image bacteria in living organisms will improve the diagnosis of infection. It will also allow for the non-invasive monitoring of bacterial responses to antibiotic treatment in humans.
  • Understanding Optogenetics for Gene Control - Photoreceptors are proteins in humans, bacteria, and plants that respond to light. Dr. Tonge and his team are exploring novel ways to control gene transcription (turning genes on and off) with light. Many organisms sense and respond to light using photoreceptors that convert the energy in a photon of light into a biological signal. Dr. Tonge and his team are using novel spectroscopic methods to understand how photoreceptors work in order to drive the development of novel photoreceptors that can be used to turn genes on and off with light. Such optogenetic devices will have important implications in treating diseases.

Bio

Dr. Peter Tonge has always had an insatiable desire to understand the world around him. When he was 10 years old, his parents bought him a chemistry kit that catalyzed his interest in chemistry. In high school, Dr. Tonge took biochemistry courses, during which he became fascinated about the chemical reactions inside living organisms. He pursued biochemistry at Birmingham University in England, where he obtained his BSc and Ph.D. He then performed a two-year fellowship studying how enzymes work at the National Research Council in Canada. Enzymes are biological catalysts, and Dr. Tonge was fascinated by the ability of enzymes to catalyze chemical reactions millions of times faster than human-made catalysts. He enjoyed it so much that he stayed and continued to work there for a number of years.

Dr. Tonge then transitioned to Stony Brook University, where he continued to study enzyme function, but now in the context of human disease. He originally wanted to create enzyme inhibitors for drug development, but soon realized the huge challenges in making a successful drug. This led Dr. Tonge to think about why drug development often fails, and what was missing in understanding how drugs work. Because understanding the way drugs work enables researchers to make improved drugs he decided to pursue the science of drug discovery. Without a fundamental understanding of drug action the only alternative is to just make compounds and see which ones work.

“Why do people become scientists?” Dr. Tonge asks. “They become scientists because they're curious.” He feels very fortunate working in an academic environment where he can explore his scientific creativity and satisfy that curiosity in the lab with his students.

When he's not in the lab, Dr. Tonge enjoys running, playing squash, listening to music, and reading. 

Patents

Diphenyl Ether Antimicrobial Compounds

Inventors: Tonge PJ, Sullivan T, Johnson F. Issued 2005.

Thiolactone antibiotics

Inventors: Tonge PJ, Machutta C, Bommineni GR, Kapilashrami K. Issued 2012.