pf-429242 and Zika-Virus-Infection

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus of African origin that is transmitted by Aedes mosquitoes. ZIKV was historically limited to Africa and Asia, where mild cases were reported. However, ZIKV has recently been responsible for major global outbreaks associated with a wide range of neurological complications. Since no antiviral therapy exists for ZIKV, drug discovery research for ZIKV is crucial. Intracellular lipids regulated by sterol regulatory element-binding proteins (SREBPs) are important in flavivirus pathogenesis. PF-429242 has been reported to inhibit the activity of site-1 protease (S1P), which regulates the expression of SREBP target genes. Our primary objective in this study is to elucidate the mechanism of the antiviral activity of PF-429242 against the African genotype (ZIKV

Topics: Animals; Antiviral Agents; Cell Line; Fenofibrate; Lipogenesis; Monocytes; Neurons; Pyrrolidines; 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

Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-

Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; HeLa Cells; Humans; Lipid Metabolism; Masoprocol; Pyridines; Pyrrolidines; Sterol Regulatory Element Binding Proteins; Thiazoles; Vero Cells; Virus Replication; West Nile Fever; West Nile virus; Zika Virus; Zika Virus Infection