l803087 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

Somatostatin-14 (SRIF) is a potent anticonvulsant in rodent models of limbic seizures in which the hippocampus is its major site of action. However, the distribution of hippocampal sst receptors and their role in the anticonvulsant effects of SRIF remain controversial. Moreover, striking differences have been described between mice and rats. In rats, sst(2) but not sst(1) receptors play a critical role in the anticonvulsant effects of SRIF. At present, the role of rat sst(3) and sst(4) receptors in these anticonvulsive effects remains unknown. Here we demonstrate in vivo anticonvulsive actions of rat hippocampal sst(3) and sst(4) receptors. Using microdialysis and telemetry-based electroencephalographic recordings we show that intrahippocampal administration of the sst(2) agonist L-779,976 (500 nM), the sst(3) agonist L-796,778 (100 nM) or the sst(4) agonist L-803,087 (100 nM) protects rats against focal pilocarpine-induced seizures. SRIF (1 μM)-, sst(3)- and sst(4)-mediated anticonvulsive actions are reversed by the selective sst(2) receptor antagonist cyanamid 154806 (100 nM). Moreover, the selective sst(3) antagonist SST3-ODN-8 (100 nM) blocks the sst(4)-mediated anticonvulsant effect. Sst(3) antagonism does not reverse the sst(2)- or SRIF-mediated anticonvulsant effects. Our findings provide the first in vivo evidence for potent anticonvulsive properties of sst(3) and sst(4) receptors in the rat hippocampus. Nevertheless, selective sst(2) receptor antagonism prevented these sst(3)- or sst(4) receptor-mediated anticonvulsant effects, suggesting a functional cooperation with rat hippocampal sst(2) receptors.

Topics: Amides; Analysis of Variance; Animals; Anticonvulsants; Chromatography, Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Hippocampus; Indoles; Male; Microdialysis; Nitrobenzenes; Pilocarpine; Rats; Rats, Wistar; Receptors, Somatostatin; Seizures; Somatostatin