st-1936 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

Serotonin 5-HT(6) receptor agonists and antagonists have been proposed as possible useful compounds in the treatment of psychiatric disorders such as depression. This study was aimed at characterizing ST 1936, a new 5-HT(6) receptor agonist, as a possible antidepressant/anti-anhedonic drug by studying its effects on three experimental models of depression. These models are based on the behavioral sequelae induced in rats by unavoidable stressors that result in decreased reactivity to avoidable stressors (escape deficit, ED) and an anhedonia-like condition based on the disruptive effect of stress on the competence to acquire an instrumental vanilla sugar-sustained appetitive behavior (VAB). The repeated administration of ST 1936 prevented the development of ED, but did not revert a condition of chronic ED. The protective effect of ST 1936 was antagonized by co-administration of SB 271046, a 5-HT(6) receptor antagonist, indicating that the 5-HT(6) receptor stimulation is crucial for triggering a plasticity process that resulted in the prevention of ED development. ST 1936 administration in rats undergoing VAB training did not interfere with its acquisition, whereas SB 271046 administered in similar conditions prevented VAB acquisition. Moreover, ST 1936 administration in rats trained in the Y-maze while exposed to a chronic stress protocol consistently antagonized the stress-disrupting effect, and also this effect was antagonized by SB 271046 coadministration. It was concluded that a tonic 5-HT(6) receptor activity was crucial for VAB acquisition, and that pharmacological stimulation of 5-HT(6) receptors reinstated a stress-reduced hedonic competence with an efficacy similar to that of classical antidepressant drugs.

Topics: Analysis of Variance; Animals; Appetitive Behavior; Benzazepines; Depression; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Electroshock; Escape Reaction; Ethylamines; Food Preferences; Indoles; Male; Motor Activity; Pain Threshold; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Serotonin Receptor Agonists; Sweetening Agents; Time Factors