Hepatitis C Virus Translation Inhibitors Targeting the Internal Ribosomal Entry Site

Dibrov, Sergey M.; Parsons, Jerod; Carnevali, Maia; Zhou, Shu; Rynearson, Kevin D.; Ding, Kejia; Sega, Emily Garcia; Brunn, Nicholas D.; Boerneke, Mark A.; Castaldi, M. Paola; Hermann, Thomas

doi:10.1021/jm401312n

Cited by 75 publications

(95 citation statements)

References 127 publications

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“…Internal loops and bulges that occur within the Hepatitis C IRES have been extensively studied as known drug target sites (Kikuchi et al 2005;Davis and Seth 2011;Dibrov et al 2014). In vitro studies and crystal structures demonstrate that small molecules such as benzimidazole bind to the loop motifs within the HCV IRES, induce a conformational change, and effectively inhibit viral translation (Paulsen et al 2010;Dibrov et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Advancing viral RNA structure prediction: measuring the thermodynamics of pyrimidine-rich internal loops

Phan

Mailey

Saeki

et al. 2017

RNA

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Accurate thermodynamic parameters improve RNA structure predictions and thus accelerate understanding of RNA function and the identification of RNA drug binding sites. Many viral RNA structures, such as internal ribosome entry sites, have internal loops and bulges that are potential drug target sites. Current models used to predict internal loops are biased toward small, symmetric purine loops, and thus poorly predict asymmetric, pyrimidine-rich loops with >6 nucleotides (nt) that occur frequently in viral RNA. This article presents new thermodynamic data for 40 pyrimidine loops, many of which can form UU or protonated CC base pairs. Uracil and protonated cytosine base pairs stabilize asymmetric internal loops. Accurate prediction rules are presented that account for all thermodynamic measurements of RNA asymmetric internal loops. New loop initiation terms for loops with >6 nt are presented that do not follow previous assumptions that increasing asymmetry destabilizes loops. Since the last 2004 update, 126 new loops with asymmetry or sizes greater than 2 × 2 have been measured. These new measurements significantly deepen and diversify the thermodynamic database for RNA. These results will help better predict internal loops that are larger, pyrimidine-rich, and occur within viral structures such as internal ribosome entry sites.

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Section: Introductionmentioning

confidence: 99%

Advancing viral RNA structure prediction: measuring the thermodynamics of pyrimidine-rich internal loops

Phan

Mailey

Saeki

et al. 2017

RNA

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“…1A) (6). Domain II is nearly 100% conserved in clinical isolates (7) and has analogous counterparts in other viral IRES elements, all of which display some secondary structure similarity, but significant sequence variation in the subdomain IIa-like internal loop (Fig. 1B).…”

mentioning

confidence: 97%

“…1D) that bind to the internal loop and block translation by capturing distinct conformational states of the RNA (7). Structure analysis revealed that benzimidazole inhibitors such as compound 1 (19,20) interact with an extended architecture of IIa in which the stems flanking the internal loop are coaxially stacked on both sides of the ligand-binding pocket ( Fig.…”

mentioning

confidence: 99%

Functional conservation despite structural divergence in ligand-responsive RNA switches

Boerneke¹,

Dibrov²,

Gu³

et al. 2014

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

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An internal ribosome entry site (IRES) initiates protein synthesis in RNA viruses, including the hepatitis C virus (HCV). We have discovered ligand-responsive conformational switches in viral IRES elements. Modular RNA motifs of greatly distinct sequence and local secondary structure have been found to serve as functionally conserved switches involved in viral IRES-driven translation and may be captured by identical cognate ligands. The RNA motifs described here constitute a new paradigm for ligandcaptured switches that differ from metabolite-sensing riboswitches with regard to their small size, as well as the intrinsic stability and structural definition of the constitutive conformational states. These viral RNA modules represent the simplest form of ligand-responsive mechanical switches in nucleic acids.

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“…Much effort has been dedicated to the development of drugs that could impair IRES-mediated translation as a means of blocking viral replication, mainly focusing on the HCV IRES (Dibrov et al 2012(Dibrov et al , 2014. Recently it has been proposed that cap-independent expression of vFLIP could provide a mechanism to control the balance between vCyclin and vFLIP levels, thereby allowing vFLIP to suppress autophagy and inhibit senescence during latent infection (Leidal et al 2012).…”

Section: Vflip Ires Activity Requires Eif4g and Eif4ementioning

confidence: 99%

Functional analysis of Kaposi's sarcoma–associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation

Othman

Sulaiman

Willcocks

et al. 2014

RNA

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Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus, the etiological agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). One of the key viral proteins that contributes to tumorigenesis is vFLIP, a viral homolog of the FLICE inhibitory protein. This KSHV protein interacts with the NFκB pathway to trigger the expression of antiapoptotic and proinflammatory genes and ultimately leads to tumor formation. The expression of vFLIP is regulated at the translational level by an internal ribosomal entry site (IRES) element. However, the precise mechanism by which ribosomes are recruited internally and the exact location of the IRES has remained elusive. Here we show that a 252-nt fragment directly upstream of vFLIP, within a coding region, directs translation. We have established its RNA structure and demonstrate that IRES activity requires the presence of eIF4A and an intact eIF4G. Furthermore, and unusually for an IRES, eIF4E is part of the complex assembled onto the vFLIP IRES to direct translation. These molecular interactions define a new paradigm for IRES-mediated translation.

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Hepatitis C Virus Translation Inhibitors Targeting the Internal Ribosomal Entry Site

Cited by 75 publications

References 127 publications

Advancing viral RNA structure prediction: measuring the thermodynamics of pyrimidine-rich internal loops

Advancing viral RNA structure prediction: measuring the thermodynamics of pyrimidine-rich internal loops

Functional conservation despite structural divergence in ligand-responsive RNA switches

Functional analysis of Kaposi's sarcoma–associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation

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