Repurposing host-based therapeutics to control coronavirus and influenza virus

Abstract

The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.

Figure 1

Scheme of targeting CoV and IFV infection by host-based repurposed drugs. CoV entry into cells relies on either a nonendosomal pathway or the endosomal pathway involving the host protease TMPRSS2 or the host adapter protein clathrin, respectively. IFV entry utilizes the endosomal pathway or the macropinocytic pathway. These pathways render the release of vRNA into the cytoplasm, followed by importing vRNA into the nucleus for viral replication. The host protein kinases Raf, Mek, Erk and CDKs have important roles in regulation of transcription and translation at various stages of viral replication. CoV and IFV utilize the host eIF-involved cap-dependent translational machinery to produce viral proteins. Activation of the host protein kinases PKR, PERK, HRI and GCN2 can phosphorylate the eIF2α to attenuate translation. Assembly of viral particles requires the host TMPRSS2 for cleavage of CoV spike and IFV HA in the Golgi apparatus to produce viral progeny to be released by budding. In addition, the NF-κB pathway is activated through inactivation of IκBa to induce proinflammatory cytokines, such as IFNs, for innate immune response to viral infection. These host-based pathways are targetable by repurposed agents to control viral infection. Representative repurposed drugs have a pink background. Green thick arrows indicate induction. Green thick stop signs indicate inhibition. Scissor signs indicate proteolytic cleavage.