Research Areas for Medicinal Chemistry
- Antiviral Drug Discovery
- Chemical and Biological Sensor Development
- Drug Discovery Research
- Natural Product Research
- Natural Products Drug Discovery
- Medicinal Chemistry
- Molecular Simulation
- Protein Chemistry
- RNA Modification
- Synthetic Biology
- Structure Based Drug Design
- RNA Targeted Therapeutics
Faculty Research Areas
Heparan Sulfate Proteoglycans: Biosynthesis, Structures and Functions
In the post-genomics era, it is now accepted that complex glycoconjugates such as proteoglycan regulate numerous patho-physiological processes in all living species. They carry enormous structural information in terms of sulfation, epimerization, domain organization, chain length, number of chains and type of chains along with their core proteins. Production of proteoglycans with such high complexity occurs in template-independent fashion seamlessly, yet our understanding of their biosynthesis, structures and functions is somewhat incomplete and imperfect. We are developing a wide variety of chemical biology tools to define the biosynthetic pathways of heparan sulfate and related glycosaminoglycans (GAG) such as chondroitin sulfate and dermatan sulfate.
Chemical probes for visualizing PTP activity
Protein tyrosine phosphatases (PTPs) play critical roles in cellular signaling, regulating tyrosine phosphorylation through hydrolysis of the tyrosine phosphate in a temporally, spatially and regioselectively controlled manner. In contrast to their counterparts, the protein tyrosine kinases (PTKs), the substrate selectivity, biological regulation and specific roles of PTPs are relatively poorly understood. However, aberrant phosphotyrosine-dependent cellular signaling plays an important role in many human diseases, including cancer, diabetes and autoimmunity. PTK-targeted drugs have hit the market with considerable success as anticancer agents, but no PTP-targeted drugs have been developed to date. In this project, our aim is to develop novel PTP-targeted chemical probes that can be used to elucidate the biological roles of PTPs and can serve as lead compounds in the development of PTP-targeted therapeutics. For example, we designed the phosphocoumaryl amino acid pCAP as a fluorogenic phosphotyrosine mimic. This probe has been invaluable in allowing us to profile the substrate selectivity of PTPs, perform several high-throughput screens to identify novel PTP inhibitors, and visualize PTP activity both directly in cells and in cell lysates through polyacrylamide gel electrophoresis. Current work includes characterizing and optimizing the new inhibitors we have discovered and developing novel activity-based probes for PTPs.
Understanding the biological action of metal-based drugs
While the majority of drug molecules are organic compounds, several very successful drugs contain metal ions. Certainly the most well-know (and well-studied) example is cisplatin, a platinum containing anticancer agent, but other examples include auranofin, a gold-containing antiarthritic agent; Pepto-BismolÂ®, a bismuth-containing treatment for gastrointestinal problems; and imaging agents such as magnevist (a gadolinium-based MRI contrast agent) and cardiolyte (a technetium-based radioimaging agent). In our lab, we have been studying the ability of auranofin and auranofin analogs to inhibit enzyme activity as one possible mechanism of action in the body. Au(I)-based compounds such as auranofin inhibit thiol-dependent enzymes, and we have demonstrated that, by tuning the ligands bound to the Au(I) ion, we can tune the selectivity and potency of the Au(I)-mediated inhibition. The relative potencies and selectivities of the new complexes hold up not only in vitro but also in vivo.
Designing redox sensors
A recent area of emphasis for our lab is the development of fluorogenic chemical probes that can be used to image the production of redox active species in vivo. Our first efforts in this field are aimed at developing hydrogen peroxide sensors that can be delivered to a specific subcellular location (i.e. the cell surface, the cytosol, the mitochondria, etc.) and at developing hydrogen sulfide sensors based on fluorogenic organometallic compounds.
The long-term goal of our research is design and development of digital therapeutics (mobile medical apps and videogames) which integrate non-pharmacological interventions with pharmaceutical drugs. Since mobile apps and videogames have become FDA-approved software as medical device, we aim to develop drug-device combination products targeting a specific chronic disease at both molecular and behavioral levels.
Why do we focus on developing digital therapeutics? Because:
They can mitigate limitations of pharmaceutical drugs (adverse effects, non-adherence, drug-resistance, affordability, shortages)
Mobile app-based treatments can improve sustainability of health care by delivering self-care and promoting prevention of chronic medical conditions
Digital transformation in medicine and health care has been happening.
Our research has advanced development of neuropeptide-based drug leads for the treatments of epilepsy and pain. This collaborative project with Prof. Steve White and Prof. Cameron Metcalf yielded several galanin-based lead compounds such as NAX 505-5, NAX 409-9 and NAX 810-2 (a candidate for Investigational New Drug (IND) for the treatment of epilepsy). Noteworthy, our galanin-based compounds also exhibit analgesic properties, offering opportunities to develop first-in-class therapies for inflammatory and chronic pain.
The people in our lab use and develop molecular dynamics, free energy simulation, and trajectory analysis methodologies in applications aimed at better understanding biomolecular structure, dynamics and interactions. A strong focus of our funded efforts centers on the reliable representation of nucleic acid systems (DNA and RNA) in solution. For example, we helped solved the NMR structure of the drug-bound Hepatitis C virus IRES structure shown on the left. Based on this (and related structures), we can now apply CADD methods and simulation to better understand and design potential new Hepatitis C therapeutics. In addition, large efforts are underway to better characterize RNA structure and force fields through simulation of a large number of commonly observed RNA structural motifs and a large variety of NMR and crystal structures. We are also involved with international collaborative efforts to understand DNA structure, for example through the ABC consortium and long simulations of DNA...
Critical to reliable representation of the structure, dynamics and interactions is not only trying to simulation the biomolecules in their native solution environment but to also both critically assess and validate the simulation results with experiment. Our group focuses on both brute-force and enhanced sampling/ensemble-based simulation using available high performance computational resources at the University of Utah (www.chpc.utah.edu) and elsewhere. Outside resources include large allocations of computer time from Blue Waters, XSEDE (www.xsede.org), on the Anton machine at PSC and from other sources. With these resources we also are able to expose and overcome limitations in the methods and force fields...
Beyond nucleic acids, we are also interested in various coiled-coils, enzymes and cytochrome P450's. A key emphasis is on improving stability or understanding how ligands alter receptor structure upon binding. Also, in addition to continued development of the ptraj/cpptraj tools within the AmberTools suite for analysis of MD trajectories, we are exploring methods to mine more information from the simulation data and means to more broadly disseminate the MD results.
The eukaryotic genome is regulated by a variety of epigenetic mechanisms that establish and maintain proper gene expression profiles to control cell identity and fate. One of these vital mechanisms is accomplished by chromatin, which is the packaging medium for genomic DNA. The chromatin polymer consists of individual nucleosomes in which the DNA is wrapped around an octamer of the canonical histone proteins H2A, H2B, H3, and H4. The histone proteins are highly post-translationally modified, and these modifications (PTMs) have an impact on the local chromatin environment through both direct biophysical perturbations and recruitment of downstream effectors. Different PTM chemotypes (e.g., methylation, acetylation, ADP-ribosylation) at different sites within the histones act as dynamic signals to delineate specific chromatin states. Thus, far from being a passive scaffold for the genome, chromatin actively controls access to the underlying genetic material to aid in regulating transcription, translation, and repair. Importantly, when histone PTMs and other epigenetic factors are disrupted, these processes are misregulated leading to diseases such as cancer and developmental disorders.
Our lab and others are trying to understand how the deposition, removal, and recognition of these PTMs are regulated and what downstream effects these PTMs have on DNA-mediated processes. In particular, our focus is studying how metabolism is linked to genomic regulation via the metabolites that fuel chromatin dynamics. We seek to elucidate mechanisms by which the metabolic state of the cell (e.g., acetyl-CoA level) is reported to the genome via chromatin (e.g., histone acetylation) to lead to changes in DNA transcription, translation, or repair. To do so, my lab will utilize a range of techniques across organic chemistry, peptide/protein chemistry, biochemistry, and molecular and cell biology.
Some project areas include 1) biochemical and in cell characterization of mechanisms by which the histone deacetylases called sirtuins sense and report on cellular metabolism, 2) development of fluorescent sensors for metabolites and histone post-translational modifications (PTMs) for obtaining detailed metabolite/PTM profiles in live cells, 3) investigation of NAD+ and ATP dynamics during the DNA damage response, and 4) characterization of mechanisms for the subnuclear localization of metabolic enzymes and development of strategies to target this localization.
DNA-encoded libraries: Streamlining drug discovery
One of the key steps in developing a new drug is to identify molecules that bind to a putative therapeutic target. However, there is a near-unlimited number of possible molecules and to identify the right one is a formidable challenge.
One approach to achieve this goal is to tag compounds with DNA strands whose sequence encodes for the structure of each compounds. In this way it is possible to use target proteins immobilized on surfaces as baits to fish for compounds that bind to this protein. Sequencing the attached DNA codes then allows to identify the corresponding molecules. In fact, this approach provides a semi-quantitative estimation of the target affinity of each compound in the library.
Such DNA-encoded libraries are nowadays used routinely in drug discovery at pharmaceutical companies. However, the prospect of this method remains largely untapped in academic medicinal chemistry efforts because of the costs associated with generating large library platforms and the validation of multiple hit compounds. We aim to overcome this problem by generating libraries that are structurally designed with specific protein families in mind. In this way, we can achieve consistent screening success at a fraction of the costs of large one-fit-all DNA-encoded library platforms.
Using such libraries, we were able to discover high potency hit compounds for several enzymes with speed and cost-efficiency unachievable by conventional methods. In parallel, we aim to further our understanding of how to synthesize and design such library and to develop algorithms for extracting important structural data from such library screens.
Dissociative Bioorthogonal Chemistry: Activating drugs and probes on demand
Reactions between non-biological reagents that occur readily in biological systems without being disturbed by it are called bioorthogonal. Numerous bioorthogonal reactions have been developed with a focus on reactions that link two molecules together. Although less well established, bioorthogonal reactions that dissociate and release a molecule could find widespread applications in molecular tools for biological research, the development of diagnostics, and the design of innovative therapeutics.
A key focus of the Franzini group is the development of such reactions that can release molecules inside cells or living organisms. Reactions thus discovered will then be applied to the development of tools to study cellular processes and new targeted therapeutics for cancer therapy.
Marine microbiology and marine biotechnology
Marine Invertebrate symbioses: Well known for in-depth studies of marine invertebrate symbioses, particularly the association between the bryozoan Bugula neritina and its symbiont Endobugula sertula, which produces the anticancer bryostatins to protect the bryozoan’s offspring from predation. Due in large part to our work, this is now the best-understood example of a marine chemical defense symbiosis. More recently, demonstrated that shipworm symbionts, in addition to their known nutritional role, also contribute bioactive secondary metabolites to the association.
Iron acquisition by marine bacteria: Long term collaboration with Alison Butler of UC Santa Barbara on siderophores, molecules used in iron binding and transport, in marine bacteria. Established the prevalence of a new class of amphiphilic siderophores typical in marine bacteria.
The mission of our laboratory is to understand the origin of chemical diversity, and to apply that diversity to drug discovery and the synthetic biology of new materials to serve human health.
We are funded by National Institutes of Health, Department of Defense, National Oceanic and Atmospheric Administration, National Science Foundation, and others.
Current projects include:
Biosynthesis of natural products in marine animals
RiPP biosynthesis and synthetic biology
Discovery of non-opioid drugs to treat pain
New treatments for infectious diseases
Graduate studies in the Department of Medicinal Chemistry are dedicated to research and education at the interface of the chemical and biological sciences. The graduate program is devoted to the education and training of students to become creative and independent investigators for positions in academic, industrial or government settings. Toward this end the graduate curriculum is an interdisciplinary composition of courses covering the major areas of contemporary medicinal chemistry. Students seeking admission must hold at least a B.S. degree in chemistry, biology, pharmacy, or a related area.