Abstract
Seasonal influenza virus epidemics result in severe illness, and occasionally influenza pandemics cause significant morbidity and mortality, although vaccines and anti-influenza virus drugs are available. By screening an in-house library, we identified methylthio-formycin (SMeFM), an adenosine analog, as a potent inhibitor of influenza virus propagation. SMeFM inhibited the propagation of influenza A and B viruses (IC50: 34.1 and 37.9 nM, respectively) and viruses showing reduced susceptibility to baloxavir and neuraminidase inhibitors but not T-705 (Favipiravir). However, the combination of T-705 and SMeFM inhibited the propagation of the influenza virus not in an antagonistic but in a slightly synergistic manner, suggesting that SMeFM has targets distinct from that of T-705. SMeFM induced A-to-C transversion mutations in virus genome RNA, and SMeFM triphosphate did not inhibit in vitro viral RNA synthesis. Our results show that SMeFM inhibits the propagation of the influenza virus by a mechanism different from that of T-705 and is a potential drug candidate to develop for anti-influenza drug.
Highlights
Influenza virus infection is a threat to global health due to significant morbidity and mortality
In T-705 and ribavirin, the carboxamide moiety in the base provides them with ambiguous base-pairing properties, and the mutations can be introduced when T-705 or ribavirin is incorporated into the viral template RNA
A-to-C transversion induced by SMeFM treatment was not consistent with those induced by purine analogs (Figure 6)
Summary
Influenza virus infection is a threat to global health due to significant morbidity and mortality. In addition to seasonal epidemics, influenza pandemics occur every 20–30 years caused by the new or re-emerging influenza A virus. Despite the existence of vaccines and antiviral drugs against influenza viruses, influenza epidemics and pandemics still emerge. To stop annual epidemics and future pandemics, effective vaccines and antiviral drugs against influenza virus infections are still required. Influenza A and B viruses (IAV and IBV, respectively) possess eight single-stranded negativesense RNAs as their genome (viral RNA: vRNA) (Noda et al, 2006; Nakatsu et al, 2016). The transcription and replication of the viral genome occur in the nucleus of infected cells. Viral RNA polymerases replicate vRNA via a complementary RNA (cRNA)
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