n-pentanoyl-2-benzyltryptamine 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

Melatonin, its agonists/antagonists were administered intrathecally (i.t.) before/after intradermal injection of capsaicin. Capsaicin produced an increase in the paw withdrawal frequency (PWF) in the presumed area of secondary mechanical allodynia and hyperalgesia. Melatonin agonists in the absence of a capsaicin injection decreased the PWF significantly, whereas melatonin antagonists given intrathecally alone were ineffective in the absence of a capsaicin injection. Pre-treatment with a melatonin agonist i.t. caused a reduction in the PWF after capsaicin. In contrast, the PWF increased after capsaicin with pre-administration of a melatonin antagonist i.t. Combined pre-treatment with melatonin and a melatonin antagonist i.t. prevented the change in PWF induced by melatonin alone after capsaicin. Intrathecal post-treatment with a melatonin agonist reduced the enhanced PWF that followed an injection of capsaicin, but treatment with a combination of a melatonin agonist and its antagonist did not alter the responses. The PWF was unaffected when melatonin analogs were applied i.t. at the T6 level or were injected intramuscularly adjacent to the L4 vertebra. In spinal rats, the data showed comparable effects of melatonin analogs on capsaicin-induced secondary mechanical hyperalgesia. Animal motor function tested by 'activity box' showed that motion activity was not affected by i.t. melatonin or its antagonist. These results suggest that activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia.

Topics: Administration, Topical; Afferent Pathways; Animals; Capsaicin; Disease Models, Animal; Drug Interactions; Hyperalgesia; Injections, Intramuscular; Injections, Spinal; Male; Melatonin; Neural Inhibition; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reflex; Skin; Spinal Cord; Spinal Cord Injuries; Tetrahydronaphthalenes; Tryptamines