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Molecules 2017, 22(5), 861;

Development of Optimized Inhibitor RNAs Allowing Multisite-Targeting of the HCV Genome

Instituto de Parasitología y Biomedicina “López-Neyra”, IPBLN-CSIC, PTS Granada, Av. del Conocimiento 17, Armilla, 18016 Granada, Spain
Current address: INSERM U1052, Cancer Research Centre of Lyon (CRCL), Université Claude-Bernard (UCBL), UMR_S1052, UCBL, 69008 Lyon, France.
Authors to whom correspondence should be addressed.
Academic Editor: Harri Lönnberg
Received: 19 April 2017 / Revised: 12 May 2017 / Accepted: 16 May 2017 / Published: 22 May 2017
(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)
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Engineered multivalent drugs are promising candidates for fighting infection by highly variable viruses, such as HCV. The combination into a single molecule of more than one inhibitory domain, each with its own target specificity and even a different mechanism of action, results in drugs with potentially enhanced therapeutic properties. In the present work, the anti-HCV chimeric inhibitor RNA HH363-10, which has a hammerhead catalytic domain and an aptamer RNA domain, was subjected to an in vitro selection strategy to isolate ten different optimised chimeric inhibitor RNAs. The catalytic domain was preserved while the aptamer RNA domain was evolved to contain two binding sites, one mapping to the highly conserved IIIf domain of the HCV genome’s internal ribosome entry site (IRES), and the other either to IRES domain IV (which contains the translation start codon) or the essential linker region between domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC50 values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved RNA molecules with potential clinical applications. View Full-Text
Keywords: RNA aptamer; hepatitis C virus; IRES; RNA targeting RNA aptamer; hepatitis C virus; IRES; RNA targeting

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Romero-López, C.; Lahlali, T.; Berzal-Herranz, B.; Berzal-Herranz, A. Development of Optimized Inhibitor RNAs Allowing Multisite-Targeting of the HCV Genome. Molecules 2017, 22, 861.

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