sm-21 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

In the present study, we examined the involvement of the sigma1 receptor in the inhibitory effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, compared with that of paroxetine, on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Sigma1 receptor agonists (+)-SKF 10047 and PRE-084 significantly inhibited marble-burying behavior. Sigma receptor antagonist BD 1047 and selective sigma1 receptor antagonist BD 1063 significantly attenuated the inhibition of marble-burying behavior by fluvoxamine. In contrast, selective sigma2 receptor antagonist SM-21 failed to affect the inhibition of marble-burying behavior by fluvoxamine. On the other hand, BD 1047 and BD 1063 had no effect on the inhibition of marble-burying behavior by paroxetine. These observations show that activation of the sigma1 receptor is a necessary component in the inhibitory effect of fluvoxamine on marble-burying behavior, and that the mechanism of its action is clearly different from that of paroxetine.

Topics: Animals; Behavior, Animal; Brain; Butyrates; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenediamines; Fluvoxamine; Male; Mice; Mice, Inbred ICR; Morpholines; Obsessive-Compulsive Disorder; Paroxetine; Phenazocine; Piperazines; Psychotropic Drugs; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Tropanes