Abstract
Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC50 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC50 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC50 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.
Highlights
There are four types of influenza viruses but only influenza A and B typically infect humans causing seasonal epidemics [1]
Based on the findings from GPCR and ion channel RNA interference (RNAi) screens [27], we studied a panel of druggable host genes and focused on Clopidogrel and Triamterene as two repurposed drugs that inhibit influenza A (A/WSN/33 and A/CA/04/ 09), and influenza B (Yamagata/16/1988) replication
Influenza antiviral drugs may reduce virus replication but this strategy often leads to virus resistance [23, 24]
Summary
There are four types of influenza viruses (types A, B, C, and D) but only influenza A and B typically infect humans causing seasonal epidemics [1]. Influenza A virus (IAV) is divided into subtypes based on the hemagglutinin (HA) and neuraminidase (NA) genes. Influenza A subtypes are further divided into genetic clades. Influenza B viruses (IBV) are not divided into subtypes but are classified into two lineages, i.e. B/Yamagata and B/Victoria [1]. IAV and IBV are enveloped and contain eight negative-sense single-stranded RNA genome segments encoding 10 primary viral proteins (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2) and various strain-dependent accessory proteins resulting from frameshift and alternative splicing events [2,3,4,5,6,7]. Seasonal epidemics arise from antigenic drift in the HA or NA surface proteins whereas pandemics are the result of viral genome reassortment events leading to vaccine failures [8, 9]. Vaccines are the most effective available method of control against influenza
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