Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA

Parsons, Jerod; Castaldi, M. Paola; Dutta, Sanjay; Dibrov, Sergey M.; Wyles, David L.; Hermann, Thomas

doi:10.1038/nchembio.217

Cited by 142 publications

(223 citation statements)

References 18 publications

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“…4). 150 The benzimidazole was shown to induce a conformational change in the target RNA by interhelical widening of the IRES subdomain IIa. This causes a breakdown of the critical interaction of the IRES with the host cell ribosomes that leads to an inhibition of translation of the HCV polyprotein.…”

Section: Screeningmentioning

confidence: 99%

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

2010

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The hepatitis C virus (HCV) is a global health issue with no vaccine available and limited clinical treatment options. Like other obligate parasites, HCV requires host cellular components of an infected individual to propagate. These host-virus interactions during HCV infection are complex and dynamic and involve the hijacking of host cell environments, enzymes and pathways. Understanding this unique molecular biosystem has the potential to yield new and exciting strategies for therapeutic intervention. Advances in genomics and proteomics have opened up new possibilities for the rapid measurement of global changes at the transcriptional and translational levels during infection. However, these techniques only yield snapshots of host-virus interactions during HCV infection. Other new methods that involve the imaging of biomolecular interactions during HCV infection are required to identify key interactions that may be transient and dynamic. Herein we highlight systems biology based strategies that have helped to identify key host-virus interactions during HCV replication and infection. Novel biophysical tools are also highlighted for identification and visualization of activities and interactions between HCV and its host hepatocyte. As some of these methods mature, we expect them to pave the way forward for further exploration of this complex biosystem and elucidation of mechanisms for HCV pathogenesis and carcinogenesis.

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Section: Screeningmentioning

confidence: 99%

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

2010

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“…The key to achieving a better therapeutic window relies on the feasibility of modifying the compound to preferentially inhibit viral translation. In a recent HCV study, benzimidazole compounds were shown to selectively bind and induce a conformational change of viral internal ribosome entry site (IRES) RNA, which weakens the ribosome docking and ultimately leads to inhibition of IRES-driven translation in HCV (28).…”

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confidence: 99%

A Translation Inhibitor That Suppresses Dengue Virus In Vitro and In Vivo

Wang

Kondreddi

Xie

et al. 2011

Antimicrob Agents Chemother

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We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and in vivo. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its in vivo stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a C max (maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC 90 ) value of 0.96 M. In agreement with the in vivo pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.Dengue virus (DENV), a member of the Flavivirus genus from the Flaviviridae family, causes approximately 50 million to 100 million human infections annually (12). Besides DENV, many other flaviviruses are important human pathogens, including West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV). There is no clinically approved antiviral treatment for any flavivirus infection. The current treatment for flavivirus infection is only supportive. Human vaccines for flaviviruses are available only for YFV, JEV, and TBEV (12). Development of a dengue vaccine is challenging because a successful vaccine requires a balanced immune response to all four serotypes of DENV; an unbalanced vaccine could lead to enhanced virus replication mediated by serotype-cross-reactive antibodies (21). Therefore, antiviral therapy is urgently needed for treatment of flavivirus infections.The flaviviral genome is a plus-sense RNA about 11 kb in length. The genomic RNA is composed of a 5Ј untranslated region (UTR), a single open reading frame, and a 3Ј UTR. The single open reading frame encodes a long polyprotein that is cleaved by a combination of viral and host proteases into 10 viral proteins, three structural proteins (capsid [C], premembrane [prM], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins form virus particles. The nonstructural proteins, together with host factors, form a replication complex to replicate viral RNA (17). Only two of the flavivirus proteins have enzymatic activities. NS3 functions as a viral serine protease, with ...

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“…1 A and B). The domain IIa, which is a potential target of antiviral drugs that block HCV protein synthesis (16), adopts a sharply bent fold that is required for the correct spatial positioning of the HCV IRES during recruitment of host cell ribosomes (17,18). Structural analysis of the unique 90°bend in the IIa domain led us to conclude that this viral RNA motif may constitute the most compact L-shaped object, or nanocorner, that can be built from contiguous double-stranded RNA.…”

Section: Resultsmentioning

confidence: 99%

Self-assembling RNA square

Dibrov

McLean²,

Parsons³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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124

116

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The three-dimensional structures of noncoding RNA molecules reveal recurring architectural motifs that have been exploited for the design of artificial RNA nanomaterials. Programmed assembly of RNA nanoobjects from autonomously folding tetraloop-receptor complexes as well as junction motifs has been achieved previously through sequence-directed hybridization of complex sets of long oligonucleotides. Due to size and complexity, structural characterization of artificial RNA nanoobjects has been limited to low-resolution microscopy studies. Here we present the design, construction, and crystal structure determination at 2.2 Å of the smallest yet square-shaped nanoobject made entirely of doublestranded RNA. The RNA square is comprised of 100 residues and self-assembles from four copies each of two oligonucleotides of 10 and 15 bases length. Despite the high symmetry on the level of secondary structure, the three-dimensional architecture of the square is asymmetric, with all four corners adopting distinct folding patterns. We demonstrate the programmed self-assembly of RNA squares from complex mixtures of corner units and establish a concept to exploit the RNA square as a combinatorial nanoscale platform.crystallography | fluorescence | RNA structure N oncoding RNA sequences can adopt intricate three-dimensional architectures whose complexity rivals those of proteins. The folding of RNA is governed by recurring structural motifs (1), the most common of which is the double helix that involves consecutively stacked pairs of complementary nucleobases interacting via hydrogen bonds. Structural motifs in RNA often form locally without the involvement of long-range tertiary interactions (2). The synthetic combination of RNA motifs has been exploited in the design of functional and architectural RNA structures (3-5), including artificial ribosensors and RNA

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Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA

Cited by 142 publications

References 18 publications

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

A Translation Inhibitor That Suppresses Dengue Virus In Vitro and In Vivo

Self-assembling RNA square

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