A number of chemical compounds have shown in vitro activity against PIV and include: protein synthesis inhibitors (puromycin); benzothiazole derivative; 1, 2, 4-thiadiazol-2 ylcyanamide; carbocyclic-3-deezaadenosine; ascorbic acid; calcium elenolate; and extracts of
Sanicula europaea leaves. However, none of these agents have clinical applications.
1 Amantadine shows activity against PIV in high concentration in vitro, but does not decrease URI symptoms in PIV challenged adults.
1Recent work has focused on transcription inhibitors, and Mao et al have demonstrated novel small molecules (C5 and C7) with potent anti-PIV activity.
9,
39 The C protein of PIV is a multifactorial accessory protein that inhibits viral transcription and interferon signaling. Removal of the N-terminal 25 amino acids of the C-protein potentiates the inhibitory activity of the protein and shows promise as a PIV antiviral agent.
39Another approach has been to target the binding or neuraminidase function of the HN protein. The HN protein recognizes sialic acid-containing glycolipids and glycoproteins on the host target cells and allows binding to occur. It also acts as a sialidase to remove sialic acid from the virus particles to prevent self-aggregation, and work is continuing to identify novel sialic acidase inhibitors.
8 DAS181 is a novel inhaled recombinant sialidase fusion protein that interferes with the initial binding of HN with the target cell sialic acid-containing receptor. DAS181 contains the catalytic domain of actinomyces viscous sialidase and the heparin-binding domain of human amphiregulin to prolong DAS181 retention on the epithelial surface.
7,
40 The drug was developed as an antiviral agent for influenza.
41 Since sialic acid residues serve as the cellular receptors for both influenza and PIV, DAS181 has been explored for PIV antiviral activity. Compassionate use of this agent was recently reported in a 63-year-old woman with acute myelogenous leukemia (AML) post HSCT, who developed PIV pneumonia.
40 Administration of the inhaled product was associated with clinical improvement and decreased PIV shedding; however, symptoms and shedding recurred 2 weeks after stopping treatment when she presented with relapsed AML. The drug was well tolerated without discernible toxicity and is a promising new therapy for PIV infection.
The discovery of the three-dimensional structure of the PIV HN has allowed the design of inhibitors that fit into the binding site of the globular head. HN receptor interaction is not only needed for binding to the target cell but is also needed for F protein triggering and fusion.
7 Additional promising agents are HN inhibitors, BCX 2798, and BCX 2855, which bind to the conserved catalytic binding site of PIV.
42,
43 These agents effectively inhibit PIV growth in the mouse model and mice treated intranasally showed decreased PIV shedding and inflammatory histopathologic changes in the lungs.
The F protein mediates fusion of the virus and host cell and is another alternative antiviral target. Rho A, a small GTPase, facilitates syncytial formation.
44 Pastey et al reported that a Rho A-derived peptide inhibited both RSV and PIV-3 in vitro by inhibiting cell-to-cell fusion in vivo by reducing the peak titer by 100-fold in RSV-infected mice.
44 Synthetic peptides derived from heptad repeat domain of HIV gp41 have been shown to be potent inhibitors of HIV infection and fusion.
45 Because fusogenic viruses, including PIV, demonstrate amino acid sequence homology at the amino termini with HIV, researchers have investigated the possibility of finding similar functional homologues for PIV.
45 Lambert et al were successful at identifying such a peptide for PIV-3 that blocked PIV-mediated syncytia formation in cell culture.
45
