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.

中文翻译：

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通过同时靶向病毒和宿主帽 2'-O-核糖甲基转移酶来减弱 SARS-CoV-2 复制和相关炎症

SARS-CoV-2 感染周期是一个多阶段过程，依赖于宿主和病原体之间的功能相互作用。在这里，我们将针对病毒和宿主酶的抗病毒药物重新用于药物阻断病毒免疫逃逸所需的病毒 RNA 2'-O-核糖帽的甲基化。我们发现宿主帽 2'-O-核糖甲基转移酶 MTr1 可以补偿病毒 NSP16 甲​​基转移酶在促进病毒复制方面的损失。同时抑制 MTr1 和 NSP16 可有效抑制 SARS-CoV-2 复制。使用基于计算机的靶向药物筛选，我们确定了一种在体外和体内具有抗 SARS-CoV-2 活性的双特异性 MTr1/NSP16 抑制剂但有不利的副作用。我们进一步展示了针对宿主SAM循环的独立阶段提供甲基转移酶共底物的抑制剂的抗病毒活性。特别是，腺苷高半胱氨酸酶 (AHCY) 抑制剂 DZNep在体外、离体和小鼠感染模型中均具有抗病毒作用，并且与现有的 COVID-19 治疗具有协同作用。此外，DZNep 表现出强大的免疫调节作用，可抑制感染引起的过度炎症并减少离体肺纤维化标志物。因此，多特异性和代谢 MTase 抑制剂构成了尚未探索的针对 COVID-19 的治疗选择。