Current and Emerging Themes in the Structural Analysis of Viral RNA Genomes: Applications for the Development of Novel Therapeutic Drugs

Abstract

RNA molecules assume different roles in many different biological processes. This functional diversity is intimately related to RNA folding. In recent years, advances in the field of structure analysis by high-throughput methodologies and the development of novel potent bioinformatic tools have enabled the first structural maps of the eukaryotic transcriptome and the further establishment of novel function-structure relationships. This important progress has been of special relevance in the field of molecular virology. Viral genomes are compact entities that require overlapping coding levels to bear all the genetic information required for viral propagation. This is achieved by the acquisition of functional RNA domains, structurally conserved encoding units that perform essential roles for the consecution of the viral cycle. Interfering with the activity of these structural elements offers a potential means of treating viral infections, such as that caused by the hepatitis C virus, HCV. This review summarizes major achievements in the development of emerging methodologies for the analysis of RNA folding and their application to the study of the HCV genome structure. It will also examine the progress toward the design of novel antiviral compounds based in nucleic acids able to interfere with the folding of functional RNA domains.

The Role of the RNA-RNA Interactome in the Hepatitis C Virus Life Cycle

“…This interaction is stable in the absence of protein factors and induces conformational changes, not only in the directly interacting regions, but also in other distant elements of the viral genome, as demonstrated in replication competent RNA transcripts [86,116]. In subdomain IIId, the residues at the apical loop may appear partially occluded and non-accessible to the surrounding solvent because of the interaction with domain 5BSL3.2 [117]. This alternative structure may reduce the affinity of the IRES for the 40S subunit, promoting the escape of the ribosome from the IRES and impeding translation initiation.…”

The 5BSL3.2 Functional RNA Domain Connects Distant Regions in the Hepatitis C Virus Genome

“…Upper panel : Diagram of the secondary structure of the 5′ and 3′ ends of the HCV genome, including the functional domains involved in long-distance RNA–RNA contacts (solid gray lines). Middle panel : It shows the prediction for the structure of subdomain IIId ( Romero-López and Berzal-Herranz, 2015 ). Root mean-square deviation (RMSD) values reflect differences in the conformation of subdomain IIId in the presence of the IIId-5BSL3.2 interaction (right) compared to its absence (left).…”

“…Conformational consequences derived from the interaction 5BSL3.2-IIId have been mapped by chemical probing coupled to three-dimensional structure prediction ( Figure 5 ) ( Romero-López et al, 2012 ; Romero-López and Berzal-Herranz, 2015 ). The aromatic rings of the residues located in the apical loop of subdomain IIId have been reported to change their orientation with respect to the solvent because of their interaction with 5BSL3.2 ( Figure 5 ).…”