Abstract
ABSTRACT African swine fever virus (ASFV) is the causal agent of a fatal disease of domestic swine for which no effective antiviral drugs are available. Recently, it has been shown that microtubule-targeting agents hamper the infection cycle of different viruses. In this study, we conducted in silico screening against the colchicine binding site (CBS) of tubulin and found three new compounds with anti-ASFV activity. The most promising antiviral compound (6b) reduced ASFV replication in a dose-dependent manner (IC50 = 19.5 μM) with no cellular (CC50 > 500 μM) and animal toxicity (up to 100 mg/kg). Results also revealed that compound 6b interfered with ASFV attachment, internalization and egress, with time-of-addition assays, showing that compound 6b has higher antiviral effects when added within 2–8 h post-infection. This compound significantly inhibited viral DNA replication and disrupted viral protein synthesis. Experiments with ASFV-infected porcine macrophages disclosed that antiviral effects of the compound 6b were similar to its effects in Vero cells. Tubulin polymerization assay and confocal microscopy demonstrated that compound 6b promoted tubulin polymerization, acting as a microtubule-stabilizing, rather than a destabilizing agent in cells. In conclusion, this work emphasizes the idea that microtubules can be targets for drug development against ASFV.
Highlights
African swine fever virus (ASFV) is the causative agent of a devastating and economically significant disease of domestic pig
Current control methods are in place, we have seen the spread of the ASFV across Europe along with recent outbreaks in China where millions of pigs have been culled in an effort to halt its spread in 32 provinces since August 2018
To examine whether microtubule-targeting agents may disrupt ASFV infection, Vero cells were infected with the ASFV and exposed to colchicine (10 μM), paclitaxel (10 μM), nocodazole (5 μM) and vinblastine (5 μM) (Figure 1A) at non-toxic concentrations for 24 h (Figure 1S)
Summary
African swine fever virus (ASFV) is the causative agent of a devastating and economically significant disease of domestic pig. Current control methods are in place, we have seen the spread of the ASFV across Europe along with recent outbreaks in China where millions of pigs have been culled in an effort to halt its spread in 32 provinces since August 2018. These examples of continuing spread of the ASFV, considering current control measures, highlights the need for development of improved control strategies that include vaccines and antiviral drugs. Maraviroc (approved for the treatment of HIV-1 infection) acts as an antagonist of the CCR5 receptor [3]
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