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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
C Romero-LópezA Berzal-Herranz

Abstract

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 IC50values 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 obtai...Continue Reading

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Citations

Nov 17, 2017·International Journal of Molecular Sciences·Pascal RöthlisbergerMarcel Hollenstein
Oct 14, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Harri Lönnberg
Mar 16, 2019·Pharmaceuticals·Alfredo Berzal-HerranzSara Ramos-Lorente
Jul 28, 2020·Pharmaceuticals·Alfredo Berzal-Herranz, Cristina Romero-López
Jul 10, 2021·Chembiochem : a European Journal of Chemical Biology·Shu-Ichi NakanoNaoki Sugimoto

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Methods Mentioned

BETA
SELEX
transfection
phosphotransferase
PCR
in vitro transcription
size exclusion chromatography
electrophoresis

Software Mentioned

Image Quant
SigmaPlot
Rad CFX real time manager
RNAup
RNAstructure
Bio

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