Abstract
Influenza virus RNA-dependent RNA polymerase (vRdRp) does not have capping activity and relies on the capped RNAs produced by the host RNA polymerase II (RNAPII). The viral polymerases process the capped RNAs to produce short capped RNA fragments that are used as primers to initiate the transcription of viral mRNAs. This process, known as cap-snatching, can be targeted by antiviral therapeutics. Here, anthralin was identified as an inhibitor against influenza a virus (IAV) infection by targeting the cap-snatching activity of the viral polymerase. Anthralin, an FDA-approved drug used in the treatment of psoriasis, shows antiviral activity against IAV infection in vitro and in vivo. Importantly, anthralin significantly reduces weight loss, lung injury, and mortality caused by IAV infection in mice. The mechanism of action study revealed that anthralin inhibits the cap-binding function of PB2 subunit and endonuclease activity of PA. As a result, viral mRNA transcription is blocked, leading to the decreases in viral RNA replication and viral protein expression. In conclusion, anthralin has been demonstrated to have the potential of an alternative antiviral against influenza virus infection. Also, targeting the captive pocket structure that includes the N-terminus of PA endonuclease domain and the C-terminal of PB2 cap-binding domain of IAV RdRp may be an excellent strategy for developing anti-influenza drugs.
Highlights
Influenza A viruses (IAV) are enveloped viruses of the family Orthomyxoviridae that cause contagious respiratory diseases and substantial morbidity and mortality (Palese, 2007)
We found that anthralin prevents the PB2 from binding to the capped RNAs and the cleavage of capped RNAs mediated by the endonuclease activity of PA
The results showed that compared with phosphatebuffered saline (PBS) control, 50 mg/kg/d of anthralin treatment reduced the virus titers by greater than 90% in the bronchoalveolar lavage fluids (BALFs), while 25 mg/kg/d of anthralin treatment reduced the virus titers by 70% in the BALFs (Figure 1E)
Summary
Influenza A viruses (IAV) are enveloped viruses of the family Orthomyxoviridae that cause contagious respiratory diseases and substantial morbidity and mortality (Palese, 2007). Favipiravir (T-705), a new drug currently in the clinical trial, acts as a purine analog, inhibits multiple RNA viruses by targeting viral polymerase. It increases uric acid, causes digestive system diseases and has reproductive toxicity (Furuta et al, 2005; Sangawa et al, 2013; Furuta et al, 2017). The synthesis of viral mRNA, cRNA, and vRNA is the central event and crucial for influenza virus life cycle Both host factors and virus polymerase are involved in this process, during which, cap-binding, endonuclease, and vRdRp activity, are attractive targets for small molecule inhibitors. The viral polymerase of influenza virus is the target for several novel anti-influenza candidates under active clinical development (McKimm-Breschkin et al, 2018)
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