Repurposing Antifungals for Host-Directed Antiviral Therapy?

Abstract

Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. Here, we summarize what is known about the mechanisms and modes of action for a potential use of antifungals as repurposed host-directed anti-infectives for the therapeutic intervention to control viral infections.

Keywords: antifungals; azoles; drug repurposing; echinocandins; host-directed drug therapy; polyenes; viral infections.

Figure 1

Basic steps of the replication cycle of viruses in mammalian cells. Upon attachment of the virus to receptors on the host cell surface (1), viruses cross cellular membranes to gain access to the host cell, either by penetration (for nonenveloped viruses) of or fusion (for enveloped viruses) with the plasma membrane (2a) or endosomes (2b), and the viral genome is released into the host cell (3). Viral replication depends on the synthesis of viral components using the existing or modified host cell organelles (4) and the release of the newly assembled virions from the host cell via either exocytosis of virion-containing vesicles (5a) or budding (5b). To support the viral replication, viruses modulate cellular signaling pathways, such as the Wnt, Shh, VEGF, and mTORC1 signal transduction pathways (6). Repurposed drugs might target (i) viral interaction with cellular membranes (during virus internalization, assembly, release), (ii) translation and modification of viral proteins, and (iii) cellular signaling pathways hijacked by the virus to suppress virus detection and destruction and promote viral assembly and release. Adapted from “Coronavirus Replication Cycle”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates (accessed date on 15 December 2021).