To prime their own transcription, influenza A virus (IAV) and influenza B virus (IBV) use ‘cap snatching’, in which the 5′ end of fully capped host RNA is removed and attached to viral mRNAs. Deficiency in host RNA methyltransferase MTR1 — which mediates a 2′-O-methylation step required for host cap maturation — has previously been shown to enhance antiviral interferon responses to the IAV, reduce its cap-snatching efficacy and impair replication. MTR1 may therefore represent a potential target for anti-influenza drugs. Here, Tsukamoto et al. demonstrate in a human cell line that MTR1 is essential for the initiation of replication of both IAV and IBV. An in silico screen of 5,597 compounds, followed by molecular docking studies using the crystal structure of MTR1, identified the adenosine analogue, tubercidin — a natural product from Streptomyces — as an inhibitor of MTR1. Evaluation of 115 tubercidin-related compounds in antiviral drug assays revealed trifluoromethyl tubercidin (TFMT) to be the most effective non-toxic compound. TFMT inhibited replication of various strains of IAV and IBV in human bronchial epithelial cells, human lung explants ex vivo, and mice, without signs of toxicity. In vitro mechanistic studies confirmed TFMT to inhibit IAV cap snatching, acting synergistically with antivirals baloxavir marboxil and oseltamivir.
Tsukamoto, Y. et al. Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication. Science 379, 586–591 (2023)
子夜星河 