New pharmacological strategies to fight enveloped viruses

Abstract

Enveloped viruses pose an important health threat because most of the persistent and many emerging viruses are enveloped. In particular, newly emerging viruses create a need to develop broad-spectrum antivirals, which usually are obtained by targeting host cell factors. Persistent viruses have developed efficient strategies to escape host immune control, and treatment options are limited. Targeting host cell factors essential for virus persistence, or immune-based therapies provide alternative approaches. In this review, we therefore focus on recent developments to generate antivirals targeting host cell factors or immune-based therapeutic approaches to fight infections with enveloped viruses.

Keywords: antiviral agents; emerging disease; host cell factors; immunotherapy.

Figure 1

Antiviral strategies targeting host factors. Attachment of a virus to the host cell can be blocked by molecules binding to membrane components, such as SALPs binding to heparin sulfates (A). Virus entry requires high-affinity receptor binding and membrane fusion, which can be inhibited by blocking the specific receptor (B) or by disrupting the viral membrane integrity, such as LJ001 or Arbidol (C), respectively. Molecules can also modify intracellular transport pathways hijacked by the virus, such as ezetimibe altering the lipid metabolism (D). Inhibition of cellular factors involved in viral replication, for example, cyclophilin A or miR122 (E), or in viral morphogenesis, such as glucosidases (F), can decrease production and release of infectious viral particles. Abbreviation: SALPs, synthetic anti-lipopolysaccharide (LPS) peptides.

Figure 2

Antiviral mechanisms of monoclonal antibodies. Antibodies block attachment of the virus to the receptor on the host cell by either binding to viral envelope proteins (A), or to the receptor (B). Fusion of virus and cytoplasm (C), or endosome membranes (D) is prevented by antibody blocking of the fusogenic peptide. Antibodies also mediate activation of the immune system via the Fc (fragment, crystallizable) region. Opsonization of infected cells or virus particles leads to activation of the complement cascade (E). The Fc region is also recognized by Fc receptors on natural killer (NK) cells, which secrete cytokines and lyse infected cells (F), or on macrophages, which phagocytize the virus–antibody complexes (G).

Figure 3

Redirection of T cells to virus-infected cells. There are several ways how T cells might be recruited to target cells, leading to the formation of an immunological synapse, secretion of cytokines and subsequent killing of virus-infected cells. Bispecific antibodies consist of two specificities: one targeting a viral envelope protein on the surface of the infected cell and the other one targeting a molecule on the immune cell, for example, CD3 on T cells. For example, bispecific antibodies are generated by chemically linking two F(ab) (fragment, antigen binding) regions (A), or by genetically linking two scFvs (single chain fragment variable) with different specificities, so-called bispecific T cell engagers (BiTEs) (B). Viral envelope proteins can also be targeted by T cells genetically modified to express a chimeric antigen receptor (CAR) (C). This receptor consists of an scFv binding to the viral protein, a spacer domain, and intracellular CD28 and CD3ζ signaling domains. Upon antigen binding the CAR dimerizes and activation of the T cell is triggered.