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.
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HIV | HBV | HCV | |
Structure | ssRNA | Partially dsDNA | ssRNA |
Genome length | 9.8 kb | 3.2 kb | 9.4 kb |
Replication sequence | ssRNA → dsDNA → integration → ssRNA | Partial dsDNA → minus-strand dsDNA → pregenomic RNA → minus-strand RNA → positive-strand DNA → partial dsDNA | ssRNA → dsRNA → ssRNA |
Entry molecule | HIV gp/20 + CD4, HIV gp 41 + cxcR4 or CCR5 | Unknown | HCV envelope glycoproteins + (Claudin-1, occludin-1, CD81, SRB1) |
Viral proteins involved in replication | Protease, reverse transcriptase, integrase, virion infectivity factor (vif): vpr, vpu, tat, hef, rev, vpx | Enl, Enll, post-transcription regulatory element (PRE) | NS5B + NS proteins in the replication complex |
Steps inhibited by current drugs | 24 | 3 | Approx. 6 |
Integration into host DNA | Yes | No, episomal form | No |
Location of mature virion assembly | Cell membrane | Cytoplasm | Cytoplasm |
Principal host cell | CD4 + T-cell | Hepatocyte | Hepatocyte |
Half-life, infected cell | 17 h | Weeks–months | Weeks–months |
Half-life, free virus | 45 min | 3–24 h | 3 h |
Virions produced per day | 109 | 1012–1013 | 1012–1013 |
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