Mechanisms of anti-vesicular stomatitis virus activity of deazaneplanocin and its 3-brominated analogs

Gibbons, Joyce Sweeney; Khadka, Sudip; Williams, Caroline G.; Lin, Wen‐Lang; Schneller, Stewart W.; Liu, Chong; Tufariello, Jo Ann M.; Basler, Christopher F.

doi:10.1016/j.antiviral.2021.105088

Cited by 1 publication

(1 citation statement)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, it was shown to be antiviral against Ebola virus in mice (Bray et al , 2000 , 2002 ), which could be explained by a combination of interferon induction and impeded viral RNA maturation. DZNep was also shown to impair viral mRNA cap methylation in the context of vesicular stomatitis virus infection and reduce viral mRNA translation (Gibbons et al , 2021 ). Recently, DZNep was reported to be antiviral against SARS‐CoV‐2 in vitro and in ovo (Kumar et al , 2022 ), leading to viral RNA m6A methylation and cap maturation defects and consequently to reduced viral protein production and inhibition of virus replication (Kumar et al , 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of SARS‐CoV‐2 replication and associated inflammation by concomitant targeting of viral and host cap 2'‐O‐ribose methyltransferases

et al. 2022

View full text Add to dashboard Cite

The SARS‐CoV‐2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'‐O‐ribose cap needed for viral immune escape. We find that the host cap 2'‐O‐ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS‐CoV‐2 replication. Using in silico target‐based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti‐SARS‐CoV‐2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co‐substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro , in ex vivo , and in a mouse infection model and synergizes with existing COVID‐19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection‐induced hyperinflammation and reduces lung fibrosis markers ex vivo . Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID‐19.

show abstract