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

Nature Chemical Biology volume 5, pages 823825 (2009) | Download Citation

Abstract

The internal ribosome entry site (IRES), a highly conserved structured element of the hepatitis C virus (HCV) genomic RNA, is an attractive target for antiviral drugs. Here we show that benzimidazole inhibitors of the HCV replicon act by conformational induction of a widened interhelical angle in the IRES subdomain IIa, which facilitates the undocking of subdomain IIb from the ribosome and ultimately leads to inhibition of IRES-driven translation in HCV-infected cells.

  • Compound

    2,3,7,9,10,11-Hexahydro-N2,N2,N10,N10-tetramethyl-1H-pyrano[2,3-g]pyrimido[1,2-a]benzimidazole-2,10-dimethanamine

  • Compound

    3-(2-Amino-8-(hydroxymethyl)-8,9-dihydrochromeno[5,6-d]imidazol-1(7H)-yl)-2-((dimethylamino)methyl)propan-1-ol

  • Compound

    2-Aminopurine

  • Compound

    Paromomycin

  • Compound

    (S)-2-(1-Cyclohexyl-2-(furan-3-yl)-1H-benzo[d]imidazole-5-carboxamido)-3-(1H-indol-3-yl)propanoic acid

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Acknowledgements

We thank B. Ho and C. Higginson for help with compound synthesis. We acknowledge the kind gift of NS5B protein by Gilead Sciences. This work was supported in part by the US National Institutes of Health, grants R01 AI72012 (T.H.) and K08 AI069989 (D.L.W.).

Author information

Author notes

    • M Paola Castaldi

    Present address: Makoto Life Sciences, Inc., Bedford, Massachusetts, USA.

Affiliations

  1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.

    • Jerod Parsons
    • , M Paola Castaldi
    • , Sanjay Dutta
    • , Sergey M Dibrov
    •  & Thomas Hermann
  2. Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • David L Wyles

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Contributions

M.P.C. synthesized the IRES-binding benzimidazole inhibitors. S.D. synthesized NS5B inhibitors. S.M.D. participated in the design of the RNA FRET construct. J.P. performed biochemical experiments and was involved in concept development of the FRET assay. D.L.W. conceived and performed cell-based assays. T.H. conceived and supervised the project and wrote the manuscript. J.P., D.L.W. and T.H. were involved in the discussion and interpretation of the experimental data.

Corresponding author

Correspondence to Thomas Hermann.

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DOI

https://doi.org/10.1038/nchembio.217

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