4.8 Article

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Journal

SCIENCE
Volume 379, Issue 6632, Pages 586-591

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.add0875

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Scientists have discovered the importance of host RNA modification in the initiation of influenza virus replication. They found that a derivative of a natural product called TFMT can inhibit this modification and restrict influenza virus replication. TFMT acts synergistically with approved anti-influenza drugs.
Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called cap snatching. We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-L-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.

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