Chemistry Seminar Featuring : Prof. Blanton S. Tolbert, Case Western Reserve University, "Back to the Basics: Studying the Structures of RNA Viruses Offers Clues on How to Inhibit Them"

Hosted by Prof. Amanda Hargrove Abstract: Positive Strand RNA viruses persist to pose serious threats to human health and global economies. Disease progression mediated by viral pathogenesis requires numerous intersections between host proteins and viral RNA (vRNA) structures. Host-vRNA complexes drive essential processes in the replication cycles of viruses; as such, they represent untapped targets for therapeutic intervention. Members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family are cellular proteins frequently usurped by RNA viruses to modulate viral translation and genome synthesis. Moreover, recruitment of hnRNPs to viral RNA structures reprograms the cellular environment to favor optimal viral replication prior to triggering apoptosis. My lab endeavors to understand the biochemical mechanisms by which RNA viruses redirect hnRNPs to control viral gene expression. In my seminar, I will describe the biophysical basis by which the mutually antagonistic hnRNP A1 and hnRNP D (AUF1) proteins compete for the same vRNA structure to differentially regulate Enterovirus translation efficiency. Genetic mutations engineered to disrupt the structure of the bulge loop or its sequence inhibits viral replication by deregulating Cap-independent translation. I will also describe how this structure and its complex with AUF1 can be successfully targeted with small molecules to form a ternary inhibitory complex that inhibits Enterovirus replication by attenuating viral translation. Our collective knowledge is leading to the paradigm that protein-RNA cooperativity and mutual allostery manifest as idiosyncratic mechanisms that regulate viral gene expression, which in turn can be manipulated by chemical biology tools. To learn more about Prof. Tolbert's research, please visit: https://chemistry.case.edu/faculty/blanton-tolbert/