An engineered inhibitor RNA that efficiently interferes with hepatitis C virus translation and replication

Romero-López, Cristina; Berzal-Herranz, Beatriz; Gómez, Jordi; Berzal‐Herranz, Alfredo

doi:10.1016/j.antiviral.2012.02.015

Cited by 27 publications

(30 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the aptamer-ribozyme chimera did anchor to domain IV of the IRES element and inhibited in vitro and in vivo IRES-mediated translation [94]. Therefore, recruitment of ribosomal particles mediated by the IRES element was inhibited by the chimera HH363-24 that prevented both translation and replication in a hepatic cell line [95]. Moreover, to avoid HCV genome replication, Konno et al isolated RNA aptamers against the 3′ end of the negative strand of the virus genome [96,97].…”

Section: Aptamers For Virus Diagnosis and Treatmentmentioning

confidence: 99%

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

González

Martı́n

Fernández³

et al. 2016

Pharmaceuticals

View full text Add to dashboard Cite

Appropriate diagnosis is the key factor for treatment of viral diseases. Time is the most important factor in rapidly developing and epidemiologically dangerous diseases, such as influenza, Ebola and SARS. Chronic viral diseases such as HIV-1 or HCV are asymptomatic or oligosymptomatic and the therapeutic success mainly depends on early detection of the infective agent. Over the last years, aptamer technology has been used in a wide range of diagnostic and therapeutic applications and, concretely, several strategies are currently being explored using aptamers against virus proteins. From a diagnostics point of view, aptamers are being designed as a bio-recognition element in diagnostic systems to detect viral proteins either in the blood (serum or plasma) or into infected cells. Another potential use of aptamers is for therapeutics of viral infections, interfering in the interaction between the virus and the host using aptamers targeting host-cell matrix receptors, or attacking the virus intracellularly, targeting proteins implicated in the viral replication cycle. In this paper, we review how aptamers working against viral proteins are discovered, with a focus on recent advances that improve the aptamers’ properties as a real tool for viral infection detection and treatment.

show abstract

Section: Aptamers For Virus Diagnosis and Treatmentmentioning

confidence: 99%

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

González

Martı́n

Fernández³

et al. 2016

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Indeed, small RNA molecules have been proved to be efficient inhibitors targeting functional RNA genomic domains (including those at the 5′-UTR) as well as genetic products of HIV-1101112131415.Some of the inhibitory RNAs have been included in clinical trials for HIV-1 treatment16. This strategy has been also applied to other clinically relevant RNA viruses17181920.…”

mentioning

confidence: 99%

Efficient HIV-1 inhibition by a 16 nt-long RNA aptamer designed by combining in vitro selection and in silico optimisation strategies

Sánchez‐Luque

Stich

Manrubia

et al. 2014

Sci Rep

Self Cite

View full text Add to dashboard Cite

The human immunodeficiency virus type-1 (HIV-1) genome contains multiple, highly conserved structural RNA domains that play key roles in essential viral processes. Interference with the function of these RNA domains either by disrupting their structures or by blocking their interaction with viral or cellular factors may seriously compromise HIV-1 viability. RNA aptamers are amongst the most promising synthetic molecules able to interact with structural domains of viral genomes. However, aptamer shortening up to their minimal active domain is usually necessary for scaling up production, what requires very time-consuming, trial-and-error approaches. Here we report on the in vitro selection of 64 nt-long specific aptamers against the complete 5′-untranslated region of HIV-1 genome, which inhibit more than 75% of HIV-1 production in a human cell line. The analysis of the selected sequences and structures allowed for the identification of a highly conserved 16 nt-long stem-loop motif containing a common 8 nt-long apical loop. Based on this result, an in silico designed 16 nt-long RNA aptamer, termed RNApt16, was synthesized, with sequence 5′-CCCCGGCAAGGAGGGG-3′. The HIV-1 inhibition efficiency of such an aptamer was close to 85%, thus constituting the shortest RNA molecule so far described that efficiently interferes with HIV-1 replication.

show abstract

“…Indeed, different synthetic molecules targeting specific RNA motifs essential for viral RNA multiplication have been exploited as therapeutic agents. [46][47][48][49][50][51] Furthermore, the IRES-inhibitory property of IRAB was observed both in in vitro translation assays using cell free lysates and in cells transfected with infectious RNA revealing that the primary targeted event is viral RNA translation, which is IRES-dependent. 7 In agreement with this, a specific decrease of viral protein synthesis occurred in transfected cells concomitantly to a reduction in virus yield in the presence of IRAB (2 mM).…”

Section: Discussionmentioning

confidence: 99%

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

et al. 2015

View full text Add to dashboard Cite

(2015) Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation, RNA Biology, 12:5, 555-568, DOI: 10.1080/15476286.2015 The internal ribosome entry site (IRES) element located at the 5´untranslated genomic region of various RNA viruses mediates cap-independent initiation of translation. Picornavirus IRES activity is highly dependent on both its structural organization and its interaction with host factors. Small molecules able to interfere with RNA function are valuable candidates for antiviral agents. Here we show that a small molecule based on benzimidazole (IRAB) inhibited foot-andmouth disease virus (FMDV) IRES-dependent protein synthesis in cells transfected with infectious RNA leading to a decrease of the virus titer, which was higher than that induced by a structurally related benzimidazole derivative. Interestingly, IRAB preferentially inhibited IRES-dependent translation in cell free systems in a dose-dependent manner. RNA structural analysis by SHAPE demonstrated an increased local flexibility of the IRES structure upon incubation with IRAB, which affected 3 stem-loops (SL) of domain 3. Fluorescence binding assays conducted with individual aminopurinelabeled oligoribonucleotides indicated that the SL3A binds IRAB (EC 50 18 mM). Taken together, the results derived from SHAPE reactivity and fluorescence binding assays suggested that the target site of IRAB within the FMDV IRES might be a folded RNA structure that involves the entire apical region of domain 3. Our data suggest that the conformational changes induced by this compound on a specific region of the IRES structure which is essential for its activity is, at least in part, responsible for the reduced IRES efficiency observed in cell free lysates and, particularly, in RNA-transfected cells.

show abstract

An engineered inhibitor RNA that efficiently interferes with hepatitis C virus translation and replication

Abstract: Hepatitis C virus (HCV) translation is mediated by a highly conserved internal ribosome entry site (IRES), mainly located at the 5"untranslatable region (

Cited by 27 publications

References 49 publications

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

Efficient HIV-1 inhibition by a 16 nt-long RNA aptamer designed by combining in vitro selection and in silico optimisation strategies

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

Contact Info

Product

Resources

About