Influenza virus-host interactomes as a basis for antiviral drug development

Abstract

Currently, antiviral drugs that target specific viral protein functions are available for the treatment of influenza; however, concern regarding the emergence of drug-resistant viruses is warranted, as is the urgent need for new antiviral targets, including non-viral targets, such as host cellular factors. Viruses rely on host cellular functions to replicate, and therefore a thorough understanding of the roles of virus-host interactions during influenza virus replication is essential to develop novel anti-influenza drugs that target the host factors involved in virus replication. Here, we review recent studies that used several approaches to identify host factors involved in influenza virus replication. These studies have permitted the construction of an interactome map of virus-host interactions in the influenza virus life cycle, clarifying the entire life cycle of this virus and accelerating the development of new antiviral drugs with a low propensity for the development of resistance.

Figure 1

A schematic diagram of compounds that inhibit influenza virus replication and their known or putative points of action. There are two types of compound: one targets viral protein functions and the other targets host cellular functions. Examples of the former include M2 ion channel inhibitors (e.g., amantadine, rimantadine), NA inhibitors (e.g., oseltamivir, zanamivir, peramivir, and laninamivir) and viral polymerase inhibitors (e.g., favipiravir, rivavirin, and viramidine). Examples of the latter include sialidase (e.g., DAS181) [22-27], dynamin inhibitors (e.g., dynarose) [81], micropinocytosis inhibitors (e.g., EIPA) [81], MEK (MAPK/ERK kinase) inhibitor (e.g., U0126) [35,36], V-type ATPase (vacuolar-type H+ -ATPase) inhibitors (e.g., bafilomycin A) [82], protease inhibitors (e.g., aprotinin [28], which inhibits proteases that cleave cell surface HA proteins that have a single arginine at their cleavage site, and furin-like protease inhibitors, including peptidemimetics derived from decanoylated basic tetrapeptides, such as decRVKR chloromethylketone, which inhibit the HA cleavage of highly pathogenic H5 and H7 viruses [32-34] in the trans-Golgi, resulting in the inhibition of membrane fusion between the viral envelope and the endosomes), Hsp90 inhibitors (e.g., geldamycin) [83], NF-κB inhibitors (e.g., aspirin) [37], PI3K (phosphatidylinositol 3-kinase) inhibitors (e.g., LY294002) [84], ACC (acetyl-CoA carboxylase-α) inhibitors (e.g., TOFA) [85], and proteasome inhibitors (e.g., bortezomib) [86]. Compounds targeting host factors that have been shown to be involved in influenza virus replication in recent RNAi-based screens are also shown (i.e., KN93, TG003, ruxolitinib, and golgicide A) [43,47,71].

Figure 2

Overview of the strategies used to explore antiviral drugs targeting host factors involved in influenza virus replication. Various approaches, such as genome-wide screens, proteomics, transcriptomics, and lipidomics have been used to identify host factors involved in the influenza virus life cycle. More detailed experimental studies and bioinformatics analyses will help identify and prioritize host factors with potential as therapeutic targets.