l-748-337 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

β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, β

Topics: 3T3-L1 Cells; Adipose Tissue; Adrenergic Antagonists; Animals; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Lipolysis; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Neoplasms; Neoplasms, Experimental; Propanolamines; Receptors, Adrenergic, beta-3; Structure-Activity Relationship

We have previously reported that β(3)-adrenoceptor agonists dilate retinal blood vessels, but their effects on retinal neurons have been unclear. In this study, we examined the action of the β(3)-adrenoceptor agonist CL316243 against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats. CL316243 was injected into the vitreous cavity before, with, or after intravitreal NMDA injection. Seven days after NMDA injection, cell loss in the ganglion cell layer (GCL) and thinning of the inner plexiform layer were observed. The reduction in the number of cells in the GCL was diminished by injection of CL316243 at 15, 30, 60, or 120 min after NMDA injection, whereas no significant protective effect was observed when CL316243 was administered 240 min after NMDA injection. Neither preinjection of CL316243 30 min before NMDA nor simultaneous injection of CL316243 with NMDA exerted any protective effect. The β(3)-adrenoceptor antagonist L748337 almost completely abolished the protection conferred by CL316243 injection 120 min after NMDA injection. The number of parvalbumin-positive amacrine cells was decreased in eyes examined 1 day after NMDA treatment, but this was prevented by CL316243 injection at 120 min after NMDA injection. These results suggest that CL316243 exerts protective effects against NMDA-induced damage by stimulation of β(3)-adrenoceptors. β(3)-adrenoceptor agonists may be effective candidates for the treatment of retinal diseases associated with glutamate-induced excitotoxicity, including glaucoma and diabetic retinopathy.

Topics: Adrenergic beta-3 Receptor Agonists; Aminophenols; Animals; Dioxoles; Disease Models, Animal; Intravitreal Injections; Male; N-Methylaspartate; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Retinal Diseases; Retinal Ganglion Cells; Sulfonamides; Time Factors