Exploiting functional regions in the viral RNA genome as druggable entities

Abstract

The design of RNA-targeting antivirals offers a potent means in controlling viral infections. An essential prerequisite to this design depends on identifying functional RNA structures in the viral genome, as well as those that are readily accessible to drugs in cells. Techniques that probe RNA structures in situ have been developed recently including SHAPE-MaP. In this study, we report on the application of SHAPE-MaP to the Porcine Epidemic Diarrhea Virus (PEDV) RNA genome to categorize RNAs that are well folded, dynamic, or in the single strands by the combination of two parameters, SHAPE reactivity and Shannon entropy. Dynamic RNAs have the potential to fold into specific structures, and stabilizing their structures with compounds could be a new idea for drug design, which is demonstrated by the example of the G-quadruplex forming sequence. siRNAs targeting stable single-stranded RNA regions presented higher antiviral success rates. Our results show that the RNAs in the single strands could be efficient antiviral targets, and that SHAPE-MaP is an effective method to identify targetable structures in the viral RNA genomes through analysis of folding features.