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Through local secondary structures and long-range RNA\u2013RNA interactions, viral RNAs control essential steps of the viral life cycle, including translation, replication, genome cyclization, packaging, and evasion of host defenses. Over the last two decades, chemical probing approaches\u2014particularly Selective 2\u2032-Hydroxyl Acylation analyzed by a primer extension (SHAPE) and its high-throughput derivatives\u2014have transformed our ability to investigate these structures at a single nucleotide resolution and on a genome-wide scale. These technologies have revealed that viral genomes are highly structured and contain numerous functional RNA elements within untranslated regions as well as coding sequences. In this review, we summarize the main experimental strategies used to profile viral RNA architecture, with a focus on SHAPE-based methodologies and complementary approaches. We then discuss the major classes of functional RNA structures identified across diverse viral families, focusing on elements involved in translation and replication, such as internal ribosome entry sites (IRES) and cyclization elements, as well as other functional structures, including XRN1-resistant and frameshifting elements. Finally, we examine how structure-guided analyses are opening new avenues for antiviral intervention, including antisense oligonucleotides, small molecules, and RNA-degrading chimeras. Together, these advances highlight the viral RNA structure as both a key determinant of virus biology and a promising target for therapeutic innovation.<\/jats:p>","DOI":"10.3390\/v18050543","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:11:13Z","timestamp":1778271073000},"page":"543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the Structural Complexity of Viral RNAs with SHAPE to Guide Antiviral Therapeutics"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2099-7373","authenticated-orcid":false,"given":"Laura","family":"Broglia","sequence":"first","affiliation":[{"name":"RNA Systems Biology Lab, Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Canale","sequence":"additional","affiliation":[{"name":"RNA Systems Biology Lab, Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy"},{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8879-0144","authenticated-orcid":false,"given":"Andrea","family":"Vandelli","sequence":"additional","affiliation":[{"name":"RNA Systems Biology Lab, Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Gaetano","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"RNA Systems Biology Lab, Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Delli Ponti","sequence":"additional","affiliation":[{"name":"RNA Systems Biology Lab, Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrmicro3288","article-title":"Functional Long-Range RNA\u2013RNA Interactions in Positive-Strand RNA Viruses","volume":"12","author":"Nicholson","year":"2014","journal-title":"Nat. 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