sorivudine and Disease-Models--Animal

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

The effect of oral BV-araU was tested in cutaneous model infections of shaved Balb/c mice with herpes simplex virus type 1 (HSV-1). Progression of cutaneous symptoms associated with cutaneous infection with HSV-1 F strain was inhibited by BV-araU at doses of 20 and 50 mg/kg twice daily, beginning one day post-infection, resulting in significant increase in the survival rate. Onset of disease was suppressed in most animals receiving 100 mg of BV-araU per kg. BV-araU (20 mg/kg or more) also significantly increased the survival rate of mice infected with HSV-1 WT-51 strain. The efficacy of BV-araU was not affected by gender or age (6-9 weeks) of the mice. BV-araU was effective even when the treatment was started 2.5 days post-infection. The efficacy of BV-araU against F strain infection was comparable to that of acyclovir, but acyclovir showed therapeutic effects at lower doses compared with BV-araU against WT-51 strain infection. Against infection of cyclophosphamide-treated immunosuppressed mice with HSV-1 KOS(S) strain, BV-araU decreased the morbidity rate and severity of symptoms at doses of 200 and 100 mg/kg, respectively, and all mice given 50 mg of BV-araU or more per kg survived, suggesting oral efficacy can be achieved against HSV-1 infections in immunosuppressed individuals.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Arabinofuranosyluracil; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Herpes Simplex; Immune Tolerance; Male; Mice; Mice, Inbred BALB C

1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) and acyclovir were compared for their antiviral effects against herpes simplex virus type 1 (HSV-1) model infections in mice. Both drugs were not toxic to mice when they were administered orally by the same schedule used for therapeutic experiments. Brovavir was less toxic than acyclovir when injected by the intraperitoneal (i.p.) route. Marked efficacies of brovavir by either oral or i.p. administration were demonstrated in both experimental encephalitis and i.p. infection with HSV-1 WT-51 strain. Treatment with brovavir at a dose of 15 or 25 mg/kg twice daily resulted in increasing both survival rate and mean survival time of the infected mice. On the contrary, acyclovir showed only marginal effect against the experimental encephalitis. Survival rates of mice treated with brovavir were higher than those treated with acyclovir at corresponding doses with statistical significance. The superiority of brovavir was also found in the intracerebral infection with strain VR-3, a highly virulent strain for mice. Brovavir, but not acyclovir, at a dose of 200 mg/kg reduced the mortality. Acyclovir, however, were significantly effective in reducing mortality of systemically infected mice by both oral and i.p. administrations. The effective dose of acyclovir was lower than that of brovavir against i.p. infection with strain WT-51. Differences in mortality of strain VR-3-infected mice were statistically significant between acyclovir- and brovavir-treated groups.

Topics: Acyclovir; Animals; Antiviral Agents; Arabinofuranosyluracil; Disease Models, Animal; Drug Administration Routes; Encephalitis; Herpes Simplex; Humans; Male; Mice; Simplexvirus; Survival Rate