Abstract
Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.
Highlights
A serious threat is posed by viral pathogens, including clinical viruses (HIV, hepatitis viruses, etc.), natural emerging viruses, and viruses relevant to potential bioterrorism (Ebola, smallpox, etc.)
The Double-stranded RNA (dsRNA) detection domains included PKR1–181, PKR1–181 with dsRBM 1 (NTE3L), dsRBM 2 (CTE3L), or dsRBM 1 and 2 (26E3L) replaced by the dsRNA binding motif from poxvirus E3L, and RNaseL1–335
Isolated dsRNA detection domains and apoptosis induction domains were produced as negative controls
Summary
A serious threat is posed by viral pathogens, including clinical viruses (HIV, hepatitis viruses, etc.), natural emerging viruses (avian and swine influenza strains, SARS, etc.), and viruses relevant to potential bioterrorism (Ebola, smallpox, etc.). We measured the viability of normal human lung fibroblast (NHLF) cells that had been treated with PKR-Apaf DRACOs or negative controls and challenged with 130 plaque forming units (pfu) per well rhinovirus 1B (Figures 4, S2, S3).
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