Developing Novel Molecules to Influence Metals in Our Body

Understanding, manipulating, and controlling metal ions to improve diseases

Metal ions—such as copper, iron, and zinc—are important micronutrients for essential life processes, but they can also contribute to diseases. Often considered complicated and unpredictable, these elements are typically avoided in conventional drug discovery approaches. Dr. Katherine Franz, Alexander F. Hehmeyer Professor of Chemistry at Duke University, is a pioneer in understanding the dual nature of metals in biological systems. Leveraging the principles of inorganic chemistry and metallobiology, she seeks to understand how cells and organisms manipulate, acquire, and use metals in response to different conditions. In her lab, she designs novel molecules to manage and influence metal species, identifying how they interact and influence cellular processes. Fundamentally understanding the effects of those interactions can lead to improved public health in diseases such as neurodegeneration, cancer, and infection.

Dr. Franz and her interdisciplinary team of graduate students, postdoctoral fellows, and undergraduate researchers—who specialize in inorganic chemistry, biochemistry, and analytical chemistry—collaborate with researchers and biologists with expertise in specific disease areas at the Duke University School of Medicine. They focus on understanding the structural and functional consequences of metal ion coordination in biological systems, both by endogenous species and by the synthetic molecules they develop. Metal chelation (a treatment that removes heavy metals from the blood) can have unintended consequences of altering the normal and healthy status of cellular metals. Dr. Franz and her team design, synthesize, and evaluate novel molecules that are only activated to alter their metal-binding properties when triggered by an intentional stimulus or condition. These new chemical tools manipulate biological metal ion location, speciation, and reactivity to solve major biomedical and health-related issues. Having chemical control over metal chelation enables Dr. Franz and her team to control metal sequestration, enabling it to occur only when a predefined condition is fulfilled, such as the presence of a reactive species, a target enzyme, or a flash of light, depending on the molecule’s design. By matching the chemistry to conditions associated with a particular disease, they can tailor these compounds to bind metals at the disease site. Their innovative approach can ultimately be applied to develop clinical therapeutics. They aim to complete their current projects within two to five years.

Current research includes:

  • Exploring Unique Coordination Chemistry – Dr. Franz and her team are interested in fundamentally exploring unique coordination chemistry experienced by metals in changing environments. They’re looking at the way molecules bind to metal ions and identifying the unique properties that evolve from that interaction. They use different stimuli to change the metal complexes, identifying properties associated with structure or reactivity that emerge from the stimulation. They create metal complexes that respond to light in ways that can be developed into materials that change property in response to light. They also explore how mechanical force influences reactive metal species. This project is driven by the search for obtaining fundamental knowledge, and such systems could potentially be used in future biomedical or material applications. 
  • Designing Molecules for Antimicrobial Application - There is an increasing threat to public health posed by 'superbugs' that are resistant to current antibiotics. Both host cells and pathogen cells need a menu of metal nutrients for growth. This situation presents opportunities to manipulate metals as an antimicrobial strategy, but could be problematic if not nonspecific metals are targeted. Dr Franz and her team are designing stimulus-responsive agents that could overcome these barriers. These molecules exploit antibiotic-resistant bacteria, influencing them to conditionally release agents that cooperate with metals to induce toxicity. If successful, this approach could have a broad impact for devising strategies to overcome microbial drug resistance.
  • Creating Molecules to Mitigate Oxidative Stress and Degeneration - Dr. Franz and her team are designing molecules to inhibit oxidative stress, a process that causes cellular damage and contributes to various degenerative conditions. The damage primarily comes from highly reactive radicals that are propagated by metals, notably iron. To inhibit this oxidative damage, their novel molecules are designed to bind iron under conditions where oxidative damage is prevalent. In this way, the condition of oxidative damage creates its own inhibitor. The findings from this project may lead to effective therapeutics for neurodegenerative and cardiac diseases.
  • Developing Molecules for Cancer Application - Dr. Franz and her team are applying fundamental chemistry to influence the metallobiology of cancer cells. A challenge in this area is to manipulate metal compounds that target the tumor or pre-tumor site without interfering with a patient’s healthy metal status. To address this problem, they are creating site-specific molecules that exploit the unique enzymatic environment of drug-resistant cancer cells to activate anti-cancer agents that selectively kills cancer cells, without affecting normal cells.

To learn more, visit. Dr. Franz’s website at https://chem.duke.edu/labs/franz

Bio

Dr. Katherine Franz has long enjoyed working with students. She originally pictured herself teaching at a small college, following the path of her chemistry professor father. She obtained her Ph.D. at the Massachusetts Institute of Technology, and somewhere along the way realized she loves the discovery and creation that comes from the scientific research process. Dr. Franz enjoys watching students develop as scientists as much as she loves seeing the scientific results they produce along the way.

Dr. Franz and her team are motivated by the rich and seemingly endless scope for discovering, developing, and optimizing chemical tools and potential therapeutics. They believe the questions they pursue are important, interesting, and significant on their own merits, in addition to having potential ‘real-world’ applications. Dr. Franz and her team see huge untapped potential in bringing the skills, tools, and approaches of inorganic chemistry to bear on biomedical problems. She trains and guides both graduate and undergraduate students, encouraging them to use their creativity to solve problems. She considers students the creative force for future innovation, and is passionate about improving the quality of graduate education. 

When she’s not in the lab, Dr. Franz enjoys building campfires with her kids, watching them hook a fish on the end of a trout rod, experimenting in the kitchen, and catching as many Springsteen concerts with her husband as they can fit in. 

Awards

Dean’s Award for Excellence in Mentoring, 2016

Duke University Graduate School

Fellow of the Royal Society of Chemistry, 2014

Duke University Bass Society Fellow, 2014

Camille Dreyfus Teacher-Scholar Award, 2009

Alfred P. Sloan Research Fellow, 2008

NSF CAREER Award, 2005

Patents

ROS-Sensitive Iron Chelators and Methods of Using the Same

U.S. Patent No. 8236783: "ROS-Sensitive Iron Chelators and Methods of Using the Same," Inventors: Katherine J. Franz and Louise K. Charkoudian. Issued August 7, 2012.

Photolabile Caged Transition Metal Complexes and Methods of Using the Same

U.S. Patent No: 8440827: “Photolabile Caged Transition Metal Complexes and Methods of Using the Same." Inventors: Katherine J. Franz and Katie L. Ciesienski. Issued May 14, 2013.

Prochelators Useful for Inhibiting Metal-Associated Toxicity,

U.S. Patent 8680077: "Prochelators Useful for Inhibiting Metal-Associated Toxicity.” Inventors: Katherine J. Franz and Marina G. D. Leed. Issued March 25, 2014.

Prochelators for Inhibiting Metal-Promoted Oxidative Stress

U.S.Patent 8551976: “Prochelators for Inhibiting Metal-Promoted Oxidative Stress.” Inventors Katherine J. Franz and Filip Kielar. Issued October 8, 2013.

Compositions and Methods for Measuring Beta-Secretase Activity in Cells

U.S. Patent 8859223: “Compositions and Methods for Measuring Beta-Secretase Activity in Cells.” Inventors: Katherine J. Franz and Drew S. Folk. Issued October 14, 2014.