The design and implementation of novel tools for molecular medicine is necessarily a multi-discplinary endeavour, drawing on expertise from synthetic and medicinal chemistry, radiochemistry, biochemistry and molecular biology, and biomedical engineering. With an interdisciplinary team, our approach will involve the following steps:
1.Identify the malfunctioning molecular machine.
Molecular machines of interest are enzymes and bioactive small molecules, including reactive oxygen and nitrogen species (RONS), whose activities can become abnormal during disease onset or progression, or whose activities can provide very early indication of the response of the body to therapy. In addition to RONS, immediate targets of interest include the family of poly(ADP ribose) polymerases (PARPs), which have roles spanning from DNA damage sensing to bioreductive homeostasis and are culprit machines gone awry in an array of diseases spanning cancer to neurodegenerative disease. Immunohistological techniques and functional assays are utilized to identify malfunctioning machines of interest in order to inform the design of tools for molecular imaging, and/or to restore normal machine functioning.
2.Design & synthesize "smart" molecular tools.
Once a malfunctioning enzyme or bioactive small molecule is identified, imaging probes or therapeutic molecules will be designed to respond to the particular target by undergoing a chemical transformation that turns the molecular tool on. With this special quality of being "smart", the molecular tool will only become active in the microenvironment of the malfunctioning machine, permitting specific imaging of the target's activity, or eliciting a therapeutic response only in diseased tissues. For imaging, these "smart" molecular tools will reduce the background signal to increase the localization of disease, and, more importantly, will report on the activity or amount of the biomolecular target. For therapy, this approach utilizing activatable agents offers enhanced specificity by limiting often harmful side effects. The design of these "smart" tools will be informed by structure-activity studies to define substrate rules, as well as computer-aided modelling.
3.Validate & implement novel tools in disease models.
Malfunctioning subcellular machines underly a wide range of diseases and illnesses, including cancer, neurodegenerative diseases, heart disease, and drug-induced toxicity, giving our tool box a broad scope of applications. An array of advanced disease models are employed that cover cancer and the early monitoring of therapeutic response of tumors, drug-induced liver injury, atherosclerosis, and models of brain degeneration. These models allow us to validate that our novel tools can indeed report on or modulate the activity of our target biomolecules. Techniques such as PET and MRI will be used to observe these targets non-invasively in living subjects, and, in conjunction with advanced microscopy techniques (e.g. intravital and super-resolution microscopy), these methods will exhaustively characterize the "smart" mechanisms of the tools we develop. The goal of our work in the Molecular Medicine Lab is to provide new tools to help understand the role of these misbehaving machines in health and disease, and to ultimately improve human health by making these tools clinically accessible.