Inhibitors of mpox VP39 2'-O methyltransferase efficiently inhibit the monkeypox virus

Michala Zgarbová; Tomas Otava; Jan Silhan; Radim Nencka; Jan Weber; Evzen Boura

doi:10.1016/j.antiviral.2023.105714

Inhibitors of mpox VP39 2'-O methyltransferase efficiently inhibit the monkeypox virus

Antiviral Res. 2023 Oct:218:105714. doi: 10.1016/j.antiviral.2023.105714. Epub 2023 Sep 9.

Authors

Michala Zgarbová¹, Tomas Otava¹, Jan Silhan¹, Radim Nencka¹, Jan Weber², Evzen Boura³

Affiliations

¹ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
² Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic. Electronic address: jan.weber@uochb.cas.cz.
³ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic. Electronic address: boura@uochb.cas.cz.

PMID: 37689311
DOI: 10.1016/j.antiviral.2023.105714

Abstract

The RNA 2'-O methyltransferase (MTase) VP39 of the monkeypox virus (MpxV) participates in RNA capping within poxviruses. Sub-micromolar inhibitors targeting this enzyme were already reported. However, these 7-deaza analogs of S-adenosyl methionine (SAH) had not been tested in cellular assays until now. In this study, we employed plaque assays and cytopathic effect-based assays to evaluate the effectiveness of these compounds. All tested compounds demonstrated antiviral activity against MpxV, with EC₅₀ values ranging from 0.06 to 2.7 μM. Nevertheless, some of these compounds also exhibited cytotoxicity in HeLa cells, while others showed no toxicity. Notably, the non-toxic compounds featured a large aromatic substituent at the 7-deaza position, whereas the toxic compounds had a small substituent at the same position. These findings suggest that VP39 represents a bona fide target for the development of antiviral drugs against MpxV.