Carl Denard, Ph.D., an assistant professor in the University of Florida Department of Chemical Engineering, has received a National Science Foundation CAREER award. His research focuses on cellular and protein engineering to develop novel strategies to diagnose, target and fight disease.
With this award, Dr. Denard aims to discover and redesign protein molecules that can reprogram proteases. Proteases are enzymes that break peptide bonds in proteins. They are present in all organisms and play key roles in regulating cellular processes. Impaired protease regulation is often involved in several disease pathophysiology, including cancer, autoimmunity, neurodegeneration, and infectious diseases.
“Our goal is to discover molecules that can reprogram proteases associated with cancer, autoimmunity, and infectious diseases,” Dr. Denard said.
With this award, Dr. Denard and his team hope to make the process of isolating and designing these molecules more efficient. Currently, most approved protease drugs are inhibitors that bind the enzyme’s active site. These inhibitors are often nonspecific because many related proteases have similar active sites and cleave similar substrates. As a result, even though proteases represent about 10% of all therapeutic targets, many of them are undruggable with current drug development strategies. Therefore, there is a critical need to develop novel approaches to target proteases.
In addition to more specific inhibitors, Dr. Denard says we need molecules that can activate or change the specificity of proteases rather than inhibit them. Although researchers know that such molecules would interact with a protease away from its active site, a systematic approach to discover or design them remains largely elusive. In this project, the Denard lab will develop a high-throughput functional screen and characterization pipeline and leverage machine learning tools to discover small protein binders that can reprogram how proteases function.
“We think of enzymes as nanomachines and believe one can interact with parts of the enzyme to alter its function. Our high-throughput functional screen, coupled with machine learning tools, will allow us to explore a largely overlooked aspect of protease research. In many cancers, making a protease work faster or remain active longer can lead to a therapeutic benefit. Yet very few therapeutics exist to restore the function of a dysfunctional protease or to increase the activity of tumor-suppressive protease,” said Dr. Denard.
This award will also support the development of a STEM comic series on synthetic biology for K-5 students. Specifically, Dr. Denard will work with Gainesville sequential cartoonists to introduce elementary school children, particularly underrepresented minority students, to the wonders and potential of biotechnology and synthetic biology. Within this cartoon, Dr. Denard will emphasize that a diverse STEM workforce is necessary to meet the many challenges we currently face.
“Dr. Denard’s work combining high-throughput screening of natural and engineered proteases with machine learning tools has tremendous potential to speed up enzyme drug development,” said Carlos M. Rinaldi-Ramos, Ph.D., Dean’s Leadership Professor and department chair.
Dr. Denard holds a Ph.D. in chemical engineering from the University of Illinois at Urbana-Champaign and a B.S. in chemical engineering from North Carolina State University. He was a postdoctoral fellow in the Department of Chemistry at the University of Texas at Austin prior to his appointment at UF.