Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Abstract

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.

Cap snatch prevention: a novel approach to tackle influenza viruses

“…To evaluate whether MTr1 can be exploited in host-targeting anti-influenza approaches, Tsukamoto and colleagues first generated cell lines lacking MTr1 expression. 1 In these cells, replication of IAV and IBV was strongly attenuated and rescued by ectopically expressing functional but not catalytically inactive MTr1. Notably, only viral mRNA but not cellular mRNA expression was impaired.…”

“…A recent study published in Science 1 by Tsukamoto and colleagues shows that a derivative of tubercidin, a natural product from Streptomyces, selectively inhibits influenza A and B viruses (IAV and IBV, respectively). The compound targets the host RNA methyltransferase MTr1, and thus prevents viral “cap snatching” (Fig.…”

The use of trifluoromethyl tubercidin as a novel treatment of influenza in an overwhelmed health care setting: a correspondence

“…According to the World Health Organization (WHO) estimate, globally 650,000 deaths by respiratory diseases are linked to seasonal influenza each year [3] . Between 9 and 41 million illnesses, 140,000-710,000 hospitalizations, and 12,000-52,000 deaths were reported annually between the years 2010 and 2020 in the United States alone [4] .…”

“…Phase I trials would evaluate the safety profile of the drug while phase II and III trials would evaluate its efficacy and safety in patients with confirmed influenza infection. [12] Having highlighted some of these breakthroughs in the use of TFMT as a novel treatment of influenza, we, therefore, recommend its adoption in most parts of the world especially in all the overwhelmed health care settings as this would serve as an effective secondary preventive measure for patients with influenza in those settings and further limit complications that could arise from the disease, for example, myocarditis, encephalitis, myositis, rhabdomyolysis, respiratory, and kidney failure [3] . We also urge the country-men, especially the health authorities living in these overwhelmed health care settings to create more awareness on this novel agent among the physicians and make adequate research provisions for this novel agent in their respective secondary and tertiary health care centers at all cost.…”

Dual N6/C7-Substituted 7-Deazapurine and Tricyclic Ribonucleosides with Affinity for G Protein-Coupled Receptors

“…The 7-deazaadenosine (tubercidin) and pyrazolo­[3,4- d ]­pyrimidine derivatives were designed as to comprise privileged N 6 -benzyl and cyclopentyl substitutions, because these have been extensively shown to modulate GPCR affinity . In contrast, C7-substituents on 7-deazapurine nucleosides have not been thoroughly studied in the context of GPCRs, although 7-ethynyl or 7-trifluoromethyl modifications provided potent anticancer, antiparasitic, and antiviral agents. − This incited us to combine the aforementioned N 6 -substitution patterns with a 7-CF 3 or 7-ethynyl motif.…”