ar-c155858 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

Epilepsy is a chronic neurological disorder that affects approximately 50 million people worldwide. Ketogenic diet (KD) can be a very effective treatment for intractable epilepsy. Potential mechanisms of action for KD have been proposed, including the re-balance among excitatory and inhibitory neurotransmission and decrease in the glycolytic rate in brain cells. KD has been shown to have an effect on the expression pattern of monocarboxylate transporters (MCT), however, it is unknown whether MCT transport activity is affected by KD and linked to the reduction of seizures during KD. Therefore, we studied the influence of KD on MCT transport activity and the role of MCTs during epileptiform activity. Our results showed a decrease in the epileptiform activity in cortical slices from mice fed on KD and in the presence of beta-hydroxybutyrate. KD increased transport capacity for ketone bodies and lactate in cortical astrocytes by raising the MCT1 expression level. Inhibition of MCT1 and MCT2 in control conditions decreases epileptiform activity, while in KD it induced an increase in epileptiform activity. Our results suggest that MCTs not only play an important role in the transport of ketone bodies, but also in the modulation of brain energy metabolism under normal and ketogenic conditions.

Topics: 3-Hydroxybutyric Acid; Animals; Astrocytes; Brain; Diet, Ketogenic; Disease Models, Animal; Epilepsy; Gene Expression Regulation; Glycolysis; Ketone Bodies; Lactic Acid; Mice; Mice, Inbred C57BL; Microtomy; Monocarboxylic Acid Transporters; Neurons; Primary Cell Culture; Seizures; Signal Transduction; Symporters; Thiophenes; Tissue Culture Techniques; Uracil