Chemical tools are small molecules used as probes of a chemical or biological process. Studying the effects of chemical tools on a system can lead to new insight into the molecular target of the small molecule and the pathways it acts in. Chemical probes with defined targets can be attractive as drugs in clinical pharmacology. Our lab is currently developing chemical probes and state-of-the-art methology to study post-translational protein oxidation events with particular emphasis on S-modifications, such as sulfenylation, sulfinylation, and sulfhydration.
Redox signaling is a process whereby free radicals, reactive oxygen species, and other compounds act as biological messengers. A central mechanism underlying redox signaling is the oxidation of specific cysteine residues to modulate protein function. Oxidation of cysteine residues can change chemical properties, alter protein topography, and contribute to biological regulation. We seek to answer fundamental questions in the field, such as: Which redox-active components are present at which concentrations? Where in the cell are which redox conditions prevalent? Which cysteine residues in which proteins are modified under what conditions? How are biological processes influenced by thiol-based modifications?
In addition to regulating protein function, cysteine oxidation can also effective inhibitor-protein interactions and impact the clinical performance of drugs. As such, analysis of redox signaling is necessary to gain a deeper understanding of human biology and to design more effective drugs. The need for research in this area is also particularly acute in light of our increasing appreciation of the detrimental role that acquired cysteines play in genetic disorders and as driver oncogenes. Thio or redox proteomics is an emerging branch of proteomics aimed at detecting and analyzing redox-based changes within the proteome in different redox statuses. Our lab is pioneering new experimental approaches for the systematic characterization of the redox S-proteome.
Targeted covalent inhibitors are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of moderate chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a specific residue at the target site and form a bond. We are capturing the therapeutic potential of redox-regulated protein function by developing an entirely new class of covalent inhibitors that specifically target oxidized cysteine residues of key proteins involved in human diseases, including kinases and phosphatases.
A biomarker, or biological marker, generally refers to a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Oxidative stress is considered to be an important component of various diseases. We are currently developing new methods to measure the extent and nature of oxidative stress in order to identify viable biomarker opportunities for clinical use.
Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. We are currently developing several novel antioxidant-based therapeutics and exploring their efficiency in the prevention and treatment of various diseases, such as cystic fibrosis, COPD and cancer.
Protein engineering is the process of developing useful or valuable proteins. There are two general strategies for protein engineering, 'rational' protein design and directed evolution. These techniques are not mutually exclusive and we often apply both. Unnatural amino acids may also be incorporated through a new method that allows the inclusion of novel amino acids in the genetic code. We are currently developing new chemical strategies for site-specific incorporation of various cysteine and methionine 'oxoforms' into proteins.
Enzyme catalysis is the increase in the rate of a chemical reaction by the active site of a protein. The mechanism of enzyme catalysis is similar in principle to other types of chemical catalysis. By providing an alternative reaction route the enzyme reduces the energy required to reach the highest energy transition state of the reaction. The reduction of activation energy (Ea) increases the amount of reactant molecules that achieve a sufficient level of energy, such that they reach the activation energy and form the product. We are currently investigating mechanistic aspects of key sulfur-metabolizing enzymes that are essential for microbial survival and investigating their potential as novel antibiotic targets.
Antibiotic resistance occurs when an antibiotic has lost its ability to effectively control or kill bacterial growth; in other words, the bacteria are "resistant" and continue to multiply in the presence of therapeutic levels of an antibiotic. It was recently proposed that bactericidal antibiotics, besides through specific drug-target interactions, kill bacteria by a common mechanism involving the production of reactive oxygen species (ROS). Our data strongly suggests that ROS contribute to antibiotic mediated killing and that enhancing ROS production or interfering with the protection against ROS may form a novel strategy to improve antibiotic treatment.