Broad-Spectrum Antiviral Therapeutics

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.

Ebola Virus Does Not Block Apoptotic Signaling Pathways

“…8D). As reported previously (33,47), uninfected cells treated with dsCARE did not show obvious cytotoxic effects. Cell morphology was unchanged ( Fig.…”

“…Targeting of dsRNA during viral infection to specifically induce apoptosis in infected cells was previously reported by Rider et al (47). The broad-spectrum antiviral DRACO was effective against multiple viruses, including DNA, dsRNA, positive-sense RNA, and negative-sense RNA viruses, in cell culture and reduced virus titers in mice infected with influenza virus (47).…”

“…Three protein domains with well-known functions are fused to form DRACO or dsCARE: (i) a protein transduction domain to allow for easy uptake into cells, (ii) a dsRNA binding domain, and (iii) a caspase recruitment domain (CARD). Binding of DRACO or dsCARE to dsRNA leads to the activation of the CARD, inducing caspase-mediated apoptosis (33,47). Since the induction of dsRNA-dependent apoptosis was not inhibited by EBOV (Fig.…”

“…A promising approach toward the development of pan-antivirals takes advantage of the presence of dsRNA in many virus-infected cells. The recombinant proteins dsRNAactivated caspase oligomerizer (DRACO) and dsCARE have been reported to selectively induce apoptosis in cells containing virusinduced dsRNA, leading to the elimination of virus-infected cells and inhibition of virus spread (33,47). Three protein domains with well-known functions are fused to form DRACO or dsCARE: (i) a protein transduction domain to allow for easy uptake into cells, (ii) a dsRNA binding domain, and (iii) a caspase recruitment domain (CARD).…”

RNAi Therapeutic Potentials and Prospects in CNS Disease

“…It is crucial that each disease has not only a unique pattern but also the understanding for pathogenesis relating pathways and activating or inhibiting factors [112]. To introduce the DNA therapeutics into the CNS is much more complicated due to the BBB, which can be only permeable to lipophilic molecules of less than 400 Da [113].…”