Biography
Anna Marie Pyle is the Yale Sterling Professor in Molecular, Cellular and Developmental Biology and Chemistry, and she is a Howard Hughes Medical Institute Investigator. After graduating from Princeton University, she received a Ph.D. in Chemistry from Columbia University in 1990, with Professor Jacqueline Barton and then served as a postdoctoral fellow with Thomas Cech at the University of Colorado. Dr. Pyle formed her own research group in 1992 in the Department of Biochemistry and Molecular Biophysics at Columbia University Medical Center. In 2002, she moved to Yale University, where her group studies the structure and function of large RNA molecules and associated protein enzymes. Her projects focus on RNA molecular recognition by small molecules and proteins. Dr. Pyle is Past-President of the RNA Society, she is Vice-Chair of the Science and Technology Steering Committee for Brookhaven National Laboratory, and she serves on the Scientific Advisory Board of the Max Planck Institute for Multidisciplinary Sciences. She is the founder of RIGImmune Therapeutics. Pyle is the author of over 200 publications and has mentored more than 50 graduate students and postdocs.
Abstract
Discovering and targeting the highly structured RNA regulatory elements that are unique to pathogenic fungi: a promising new route to well-tolerated systemic antimicrobials
The development of potent, well-tolerated antifungal drugs that can be administered intravenously has been hampered by the fact that fungi and humans are both eukaryotes, sharing a very similar proteome. Conventional antifungal agents target protein enzymes that are closely related to enzymes essential to human metabolism, resulting in toxicity. Recently we have shown that fungi and humans are actually different in a fundamental way: they have distinct transcriptomes and RNA processing pathways, enabling one to selectively target RNA elements that are unique to fungal organisms. In addition, we have created a pipeline for identifying the highly structured riboregulatory motifs that are unique to fungal metabolism, particularly their mechanisms of RNA splicing. Here we show that the most severe types of fungal infection within the hospital setting, including Candida auris, Cryptococcus neoformans and many others, contain RNA tertiary structural elements that can be selectively targeted and inhibited with small molecules, leading to potent, broad-spectrum antifungal activity. This forms the basis of a new antifungal development strategy in which RNA targeting plays the leading role.