Dr. Jonathan T. Sczepanski works to develop and apply novel affinity reagents for targeting RNA and other endogenous (meaning produced or caused by factors within an organism) nucleic acids.
By Shana K. Hutchins, Texas A&M University College of Science
Dr. Jonathan T. Sczepanski, an assistant professor in the Department of Chemistry at Texas A&M University, has been selected to receive a National Institutes of Health (NIH) Maximizing Investigators’ Research Award (MIRA) to support his pursuit of novel nucleic acid technologies for probing ribonucleic acid (RNA) function and potentially treating RNA-mediated diseases.
The MIRA program was established in 2015 by the National Institute of General Medical Sciences (NIGMS) as a pilot experiment in funding science by better supporting investigators’ overall research programs through a single, unified grant, rather than multiple individual awards. By increasing funding stability, NIH officials hope to improve investigators’ ability to take on ambitious challenges and approach problems creatively while also giving them more flexibility to follow important new research directions as opportunities arise. The overall goal is to increase scientific productivity and improve the odds for important breakthroughs by providing funding that is distributed more widely among the nation’s most promising and highly talented investigators whose time, in turn, is less encumbered by the grant writing and management process.
Sczepanski’s five-year, $1.25 million MIRA is the first across the Texas A&M University System along with that of Dr. Yang Shen, an assistant professor in the Department of Electrical and Computer Engineering affiliated with the Texas Engineering Experiment Station-AgriLife Center for Bioinformatics and Genomic Systems Engineering, who also received an MIRA during the most recent funding cycle.
“The development of drug modalities to directly target cellular RNAs is a highly promising but largely unexplored research area,” said fellow Texas A&M chemist Dr. Wenshe R. Liu, holder of the Emile and Marta Schweikert Professorship in Chemistry. “Jon’s paradigm-shifting approach of identifying nonnative enantiomeric nucleic acids as RNA ligands will not just change the field but revolutionize it.”
Sczepanski joined the Texas A&M faculty in 2015 as the university’s second Cancer Prevention and Research Institute of Texas (CPRIT)Scholar in Cancer Research after earning his Ph.D. in chemistry at Johns Hopkins University in 2010 and subsequently completing an NIH/National Research Service Award (NRSA) Postdoctoral Fellowship at The Scripps Research Institute.
Drawing from his combined expertise in nucleic acids chemistry, molecular biology and directed evolution, Sczepanski works to develop and apply novel affinity reagents for targeting RNA and other endogenous (meaning produced or caused by factors within an organism) nucleic acids. Beyond serving as a template for protein expression, RNA is responsible for modulating multiple cellular outcomes — a function closely related to its three-dimensional structure. Furthermore, structured RNA elements play critical roles in a variety of diseases, including viral infections, cancer and neurological disorders.
Because of their well-recognized therapeutic and diagnostic potential, Sczepanski says RNA structures are ideal targets for disease intervention. He plans to use his MIRA funding to delve further into RNA’s structure-function relationship with the goal of developing new targeting technologies and therapeutics to treat RNA-mediated diseases.
“Outside of antibiotics binding the ribosome, structure-specific RNA-binding reagents are very rare,” Sczepanski says in his MIRA proposal. “Thus, developing new technologies that enable structure-specific targeting of RNA remains an important challenge in many fields.”
Nucleic acids (DNA and RNA) generally are perceived to exist in a single form: right-handed helixes made up of D-nucleotides. While at Scripps, Sczepanski helped to develop a new RNA-based enzyme (termed ribozyme) that functions on the mirror-image form of RNA composed of L-nucleotides. In other words, Sczepanski was able to specifically interface the two mirror images of RNA for the first time. His current research further exploits the concept of mirror-image nucleic acids interactions in order to develop a radically different type of affinity reagent, L-aptamers, that are capable of binding native D-RNA targets based on their unique shape rather than their underlying sequence.
“Binding RNAs based on their shape rather than Watson-Crick base pairing represents a significant departure from traditional oligonucleotide-based approaches and a major advance in aptamer technology,” Sczepanski says.
Sczepanski’s group will focus on incorporating modified nucleotides with protein-like functionality in hopes of generating a novel class of RNA-targeted antibody mimetics. Because these technological developments will be carried out in the context of disease-associated RNAs, such as oncogenic microRNAs and viral RNAs, he says the work will have an immediate impact by generating lead reagents to probe the etiology of disease and potentially develop new therapeutic strategies.
“In line with my overall research vision, we aim to determine the structure of an L-aptamer-D-RNA complex, which will provide insight into this novel mode of recognition and inform future L-aptamer design,” Sczepanski adds.
To learn more about Sczepanski’s research, visit http://www.chem.tamu.edu/rgroup/sczepanski/.
For more information about the MIRA program, go to https://www.nigms.nih.gov/Research/mechanisms/MIRA/Pages/default.aspx.
This story by Shana K. Hutchins originally appeared on the College of Science website.