Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Orthomyxoviruses and bunyaviruses utilize host RNA 5' caps for transcription via "cap snatching."
• Host 2'-O-ribose methyltransferase 1 (MTr1) modification of the cap is essential for influenza A and B virus replication.

Purpose of the Study:

• To identify inhibitors of MTr1 that restrict influenza virus replication.
• To elucidate the mechanism of action for novel MTr1 inhibitors.

Main Methods:

• In silico compound screening and functional analysis.
• Biochemical assays to assess MTr1 inhibition.
• Studies in human lung explants and mouse models.

Main Results:

• Trifluoromethyl-tubercidin (TFMT), a novel compound, was identified as an MTr1 inhibitor.
• TFMT targets the S-adenosyl-l-methionine binding pocket of MTr1.
• TFMT impairs the interaction between host cap RNAs and the viral polymerase basic protein 2 subunit.
• TFMT demonstrated efficacy in human lung explants and in vivo mouse models.
• TFMT exhibited synergistic activity with approved anti-influenza drugs.

Conclusions:

• Host MTr1 is a critical target for restricting influenza virus replication.
• TFMT is a potent inhibitor of influenza virus replication by targeting MTr1.
• TFMT represents a promising therapeutic candidate for influenza treatment, potentially in combination therapy.