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

• DOI: 10.15252/embj.2022111608
• Publication Date: 2022-07-14T10:46:49Z
• Authors: Valter Bergant; Shintaro Yamada; Vincent Grass; Yuta Tsukamoto; Teresa Lavacca; Karsten Krey; Maria‐Teresa Mühl...; Sabine Wittmann; Armin Ensser; Alexandra Herrmann; Anja vom Hemdt; Yuriko Tomita; Shutoku Matsuyama; Takatsugu Hirokawa; Yiqi Huang; Antonio Piras; Constanze A Jakwerth; Madlen Oelsner; Susanne Thieme; Alexander Graf; Stefan Krebs; Helmut Blum; Beate M Kümmerer; Alexey Stukalov; Carsten B Schmidt...; Manabu Igarashi; Thomas Gramberg; Andreas Pichlmair; Hiroki Kato
• Keywords: Inflammation; RNA Caps; 0301 basic medicine; 0303 health sciences; SARS-CoV-2; Ribose; Articles; Methyltransferases; Viral Nonstructural Proteins; Antiviral Agents; ddc:; COVID-19 Drug Treatment; 3. Good health; Mice; 03 medical and health sciences; Animals; RNA, Viral; ddc:610; EMBO19 ; EMBO23 ; Article ; Articles ; antivirals ; COVID-19 ; host-directed ; methyltransferase ; SARS-CoV-2

AbstractThe 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.