dChan - Q Origins Project Archive

There are currently two classes of antivirals available to treat IAV infection that target either the M2 ion channel (adamantanes) or viral neuraminidase (oseltamivir, zanamivir, peramivir and laninamivir) [5], [6]. However, because of the widespread resistance in circulating strains, adamantanes are rarely used today [7], [8]. Furthermore, resistance to neuraminidase inhibitors is continuously reported in newly emerging influenza viruses [5]. For instance, oseltamivir resistance was widespread among seasonal H1N1 strains in the 2008–2009 season [9]. Although the overall proportion of resistant isolates is relatively low among the A(H1N1)pdm09 virus, resistant isolates of the A(H1N1)pdm09 virus are continuously reported, and the proportion of drug-resistant cases not associated with oseltamivir exposure has increased significantly in US (74% in 2010–2011) [10], [11]. Consequently, there is a need to develop new antiviral strategies to overcome resistance.

IAV, like other viruses, require the host cell machinery to produce infectious progeny viruses. Targeting the host components essential for infection and replication therefore constitutes a promising antiviral strategy that may circumvent antiviral drug resistance [12]–[15]. One of these targets is endosomal acidification, which represents a critical step for IAV entry into cells [16], [17]. The decreased pH within endosome induces conformational changes in IAV hemagglutinin (HA) to expose the fusion peptide, thereby allowing fusion between the viral envelope and the endosome [18]. Indeed, inhibition of the V-type ATPases with the antibiotic bafilomycin A was reported to inhibit influenza A and B replication [19], [20]. Moreover, studies with the anti-malaria drug chloroquine, a weak base that inhibits endosomal acidification, have demonstrated its antiviral effects against influenza A and B viruses, Chikunguya virus, and the human immunodeficiency virus [21]–[24]. In addition, chloroquine also inhibits low pH-dependent proteases in the Golgi network that participate in the maturation of nascent viral proteins [25], [26].

Host calcium-dependent proteins also represent an interesting target, as many calcium-dependent proteins have been shown to participate in the IAV replication cycle, such as cellular PKCβII which is involved in IAV morphogenesis and ribonucleoprotein (RNP) import by regulating PKCα activity. Moreover, calnexin and calreticulin promote folding, prevent premature oxidation and oligomerization, suppress degradation of HA, and are important for efficient maturation of viral neuraminidase [27]–[32]. Consequently, drugs that affect intracellular calcium concentrations, such as verapamil, interfere with virus assembly and budding [31].

In this study, we compared the efficacy of commercially available drugs that either modulate endosomal pH or intracellular calcium concentration to interfere with IAV replication. The drugs were tested alone or in combination in MDCK cells against human, avian, and swine viruses from different subtypes.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110631