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Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

Author

Listed:
  • Jan Silhan

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Martin Klima

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Tomas Otava

    (Institute of Organic Chemistry and Biochemistry AS CR
    University of Chemistry and Technology)

  • Petr Skvara

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Dominika Chalupska

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Karel Chalupsky

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Jan Kozic

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Radim Nencka

    (Institute of Organic Chemistry and Biochemistry AS CR)

  • Evzen Boura

    (Institute of Organic Chemistry and Biochemistry AS CR)

Abstract

Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2′-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2′-O-RNA MTase with enzymes from unrelated single-stranded RNA viruses (SARS-CoV-2 and Zika) reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTase.

Suggested Citation

  • Jan Silhan & Martin Klima & Tomas Otava & Petr Skvara & Dominika Chalupska & Karel Chalupsky & Jan Kozic & Radim Nencka & Evzen Boura, 2023. "Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38019-1
    DOI: 10.1038/s41467-023-38019-1
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    References listed on IDEAS

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    1. Petra Krafcikova & Jan Silhan & Radim Nencka & Evzen Boura, 2020. "Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin," Nature Communications, Nature, vol. 11(1), pages 1-7, December.
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