New Inhibitors of Bacterial β-lactamases
John Buynak – Chemistry
Prof. John Buynak is involved in the design, synthesis, and evaluation of new inhibitors of bacterial β-lactamases, enzymes responsible for resistance to β-lactam antibiotics. He collaborates with a number of pharmaceutical companies and academic institutions with the objective of developing a broad-spectrum inhibitor as a clinically useful product. He has developed new inhibitors effective against enzymes, such as AmpC and class A and D carbapenemases, that are often not effected by current commercial inhibitors, and shown that these new inhibitors exhibit synergy when co-administered with current commercial β-lactam antibiotics against resistant microorganisms. Complexes of several of his mechanism-based inhibitors are now found in the Protein Data Bank. This structural data also serves to clarify the mechanism of enzymatic hydrolysis.
Biomarkers of Infectious Diseases/Virus-Induced Cancers and Developing Novel Antivirals
Robert Harrod – Biological Sciences
Dr. Harrod’s laboratory studies the molecular pathogenesis of human retroviruses (human
immunodeficiency virus, HIV; human T-cell leukemia virus, HTLV) with the long-term goals of
identifying biomarkers of infectious diseases/virus-induced cancers and developing novel
antivirals. His group discovered a new cellular cofactor – and candidate drug-target, which is essential for HIV gene expression and replication in chronically-infected H9-HIV-IIIB T-lymphocytes. Dr. Harrod and coworkers further provided the first evidence that the HTLV-1p30(II) protein possesses oncogenic activity and could contribute to tumorigenesis and/or disease
progression associated with the development of advanced HTLV-induced T-cell malignancies.
A Computer Assisted Drug Design Approach to Non-toxic Enediyne Anti-tumor Drug Candidates
Elfi Kraka and Dieter Cremer – Chemistry
An expert use of computer assisted drug design (CADD) can lead to a substantial reduction of cost and time for the development of a new drug. CADD can be made more powerful by an educated use of quantum chemical methods. This project is aimed at designing new nontoxic anticancer leads utilizing the enediyne-principle. This principle was developed by nature in billions of years. It is based on the ability of naturally occurring enediynes, which are produced by microorganisms found in Texan and Argentine soils, to destroy the DNA of toxic bacteria and viruses. Attempts to use the enediyne-principle as a basis for an anticancer drug have failed because the naturally occurring enediynes cannot differentiate between tumor and normal cells and, therefore, they are highly toxic. Using CADD we first investigated the biological activity of naturally occurring enediynes and then introduced modifications of the enediyne 'warhead' with the objective of making it target-specific. This work has led so far to a new anti-cancer drug model that could lead to safe, more effective cancer treatments. Currently, fine-tuning of the proposed new warheads and application of the new rational design concept to other drug design questions are under way.
Biocompatible Chemistry for Fluorescent Microscopy and Magnetic Resonance Imaging
The Lippert laboratory designs highly chemoselective and biocompatible organic transformations for use as fluorescence and magnetic resonance imaging probes. Reactive oxygen, nitrogen, and sulfur species form an extended family of small molecule mediators that often play key roles in health and disease. Despite the fact that many drugs, including Viagra, Nitroglycerin, and Avastin modulate the signaling of small molecule reactive species as part of their therapeutic action, it remains difficult to study these reactive species in their native biological context due to their short lifetimes and rapid diffusion. By designing chemistries that are compatible with fluorescence microscopy and magnetic resonance imaging, these novel reaction-based probes allow the real-time visualization of reactive species in living organisms, showing promise for clinical imaging and the identification of new drug targets.
Nanoparticles: Pharmacological Benefits or Toxic Risk?
Eva Oberdörster - Biological Sciences
Nano-sized particles (NSPs) are used as effective drug-delivery devices, medicines, sunscreens, and components of computers, clothing, and sporting equipment. The same chemical in its bulk form has strikingly different chemical properties from the nano-sized version, in large part due to induction of oxidative stress by just being so small. In the rush to develop new medical devices and consumer technologies using nano-sized particles, the potential toxicity of these particles is largely overlooked. As metabolites wash into the Waste Water Treatment System or as products are purposely deployed into the environment (sunscreen washing off, NSP remediation chemicals, etc.), it is unknown as to whether these particles accumulate or may become toxic. Using biomarkers of oxidative stress and other toxic endpoints, the benefit vs. risk of using NSPs can be assessed for both the patient/consumer and environmentally important species that are ultimately exposed.
Dendrimer Design for Drug Delivery
David Son – Chemistry
For a number of years, Professor Son’s research group has investigated the synthesis and characterization of highly branched macromolecules called dendrimers. These novel spherical compounds consist of a core surrounded by layers that increase in branching as the distance from the core increases. One of the useful properties of dendrimers is the presence of a large number of functional groups at the periphery, enabling chemical modification for tailoring of properties such as solubility or molecular recognition. The Son group has recently begun an initiative to synthesize dendrimers as drug delivery agents, either by encapsulating the active agent or by covalently attaching the agent to the dendrimer periphery. In either case, the drug can be released by an external trigger, such as a lowering of pH. The spherical geometry of dendrimers, in addition to their controllable size and solubility, make them attractive for drug delivery applications.
Nitric Oxide (NO) Redox Cell Signaling Mechanisms
Peng Tao – Chemistry
Nitric Oxide (NO) is a critical cell signaling messenger in the immune, cardiovascular and nervous systems. Due to its high reactivity and toxicity as a free radical, NO possesses a controversial effect on cell viability. The S-nitrosylation of protein thiol groups is a key mechanism in NO redox signal transduction, and lends a mechanistic basis for NO as a cell regulator. Numerous experiments have shown that the rate-limiting step of S-nitrosylation is NO autoxidation, independent of thiol concentration. Due to the transient nature and structural variety of reactive nitrogen species, very little is known about the mechanisms of either NO autoxidation or S-nitrosylation. Through the collaboration with clinical scientists, we are working on applying advanced computational methods to reveal the NO cell signaling mechanisms to answer mechanistic questions regarding this fundamental process in cell biology.
Controlled Drug Delivery and Imaging
Nick Tsarevsky – Chemistry
The Tsarevsky group focuses on the synthesis of polymers with controlled molecular weights and architectures, including linear, graft, star-like, hyperbranched, and network polymers. Additionally, the synthesized well-defined polymers are characterized with a precise placement of specific functionalities, including redox-sensitive groups and groups undergoing (bio)degradation under selected conditions, e.g., in reducing, acidic or basic environments, etc. Of particular interest are polymers with biomedical applications such as controlled drug delivery and imaging. Controlled/“living” radical polymerization techniques are employed by the group for the syntheses of well-defined polymers. Further, mechanistic studies, including determination of kinetic and thermodynamic reaction parameters are carried out that enable the rational selection of polymerization conditions (e.g., catalyst or initiating system) for the synthesis of well-defined polymers with desired structures.
Tea Compounds as Inhibitors of Metabolic Enzymes
Steve Vik – Biological Sciences
Tea leaves are a rich source of flavonoids, including compounds such as the family of catechins. During the process of making black tea the catechins are oxidized, and fuse to form theaflavins. We have recently analyzed the inhibitory properties of the theaflavins with respect to two key metabolic enzymes: the ATP synthase and Complex I of the respiratory chain. Both enzymes are inhibited by theaflavins, in particular by the 3,3¹ digallate ester. We seek to better understand the mechanism of inhibition of these and related natural products, using mutagenesis, molecular docking analysis, and computational analysis.
Structure-Function Relationships of Medically Relevant Enzymes
Pia Vogel – Biological Sciences
The Vogel group has been interested in structure-function relationships of medically relevant enzymes, such as the multidrug resistance protein family, which is thought to be one of the root causes of multidrug resistances of cancers and in treatments of infectious diseases. Another medically important enzyme we have been studying is the ATP synthase which is responsible for the generation of biologically usable energy sources. Using our expertise in enzymology and the cutting edge Electron Spin Resonance spectroscopy biophysical technique we set out to understand the molecular events that underlie protein function.
In collaboration with John Wise (SMU Biological Sciences), biochemical verification and mechanistic investigation of identified lead inhibitors for the multidrug resistant pumps are being studied. Read more about this project here.
Targeted Drug Discovery
John Wise – Biological Sciences
Our experimental approaches include unique structure elucidations of medically important target proteins using novel structural modeling techniques, molecular dynamics techniques and in silico drug docking methods to identify possible leads for drug development studies. Starting with target structures from the Protein Database or our own deduced models based on evolutionary relationships, state-of-the-art high performance computational facilities have allowed us to “bring the static structures of proteins and enzymes to life” using advanced molecular dynamics approaches. These dynamic structures better represent the real physiological target proteins of interest and are then used with virtual drug docking approaches to identify promising lead candidates from virtual libraries of millions of compounds.
In collaboration with Pia Vogel (SMU Biological Sciences), multidrug resistant pumps that are problematic in cancer chemotherapy and antiviral resistances are being investigated. “Wet lab” protein expression and biochemical screening systems to follow up on the identified leads allow verification of the in silico identified leads. Read more and see video of the 3-D computer model here.
Phosphazenes: Biocompatible Inorganic Small Molecules and Polymers
Patty Wisian-Neilson – Chemistry
Our work focuses on both cyclic small molecule and polymeric phosphazenes which are based on a phosphorus-nitrogen backbone. Through simple chemical modifications, a large variety of substituents can be attached to the phosphorus of this backbone thus allowing for control of a large range of properties. For example, hydrophobicity/hydrophilicity may be easily tuned through controlled variation of substituents, or the polymers may be designed to be biodegradable. Cytotoxicity studies of our primary polymers, i.e., poly(alkyl/arylphosphazenes), have shown them to be non-toxic and non-hemolytic. These bioinert materials lend themselves to surface functionalization that could enhance biocompatibility, adhesion, and corrosion resistance. We are also actively studying the basket-shaped, small molecule analogs of polyphosphazenes. The specific shape afforded by these molecules is of potential interest for molecular recognition. The recent attachment of an amino acid to the baskets and the polymers and the potential to incorporate simple carbohydrates will facilitate the design of synthetic bioreceptors.
Engineering Light-Activated Enzymes for Biological Manipulation
Brian Zoltowski – Chemistry
Work in the Zoltowski laboratory focuses on elucidating the structure and mechanism of blue-light photosensors. Recent research in the field of optogenetics has demonstrated the utility of reengineering photo-reactive enzymes to induce biologically relevant signal transduction pathways. Fundamental understanding of the photochemical mechanisms and activation pathways of these photosensors allows for repurposing existing optogenetic tools for new biotechnological applications. In particular the Zoltowski laboratory is interested in engineering modified blue-light photosensors for the purposes of genetic manipulation, drug delivery and precise regio- and temporal control of biological function.