rottlerin and Zika-Virus-Infection

Infection of Zika virus (ZIKV) may cause microcephaly and other neurological disorders, while no vaccines and drugs are available. Our study revealed that rottlerin confers a broad antiviral activity against several enveloped viruses, including ZIKV, vesicular stomatitis virus, and herpes simplex virus, but not against two naked viruses (enterovirus 71 and encephalomyocarditis virus). Rottlerin does not have a direct virucidal effect on the virions, and its antiviral effect is independent of its regulation on PKCδ or ATP. Both pretreatment and post-treatment of rottlerin effectively reduce the viral replication of ZIKV. The pretreatment of rottlerin disturbs the endocytosis of enveloped viruses, while the post-treatment of rottlerin acts at a late stage through disturbing the maturation of ZIKV. Importantly, administration of rottlerin in neonatal mice significantly decreased the ZIKV replication in vivo, and alleviated the neurological symptoms caused by ZIKV. Our work suggests that rottlerin exerts an antiviral activity at two distinct steps of viral infection, and can be potentially developed as a prophylactic and therapeutic agent.

Topics: Acetophenones; Adenosine Triphosphate; Animals; Antiviral Agents; Benzopyrans; Mice; Virus Replication; Zika Virus; Zika Virus Infection

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection