vuf-8430 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

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic Neurons; Animals; Benzimidazoles; Clonidine; Disease Models, Animal; Guanidines; Histamine; Humans; Injections, Spinal; Locus Coeruleus; Male; Mice; Mice, Knockout; Microinjections; Neuralgia; Norepinephrine; Pain Management; Receptors, Histamine H4; Thiourea

In the present study we examined whether histamine H(4) receptors (H(4)Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage.. The H(4)R antagonist JNJ7777120 and the H(4)R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin(IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice.. Neither JNJ7777120 nor the H(4)R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H(4)R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.).. Data obtained with selective ligands suggest that the H(4)R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H(4)R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H(4)R functions and/or new selective ligands.

Topics: Animals; Anti-Inflammatory Agents; Bethanechol; Disease Models, Animal; Guanidines; Histamine Agonists; Histamine Antagonists; Indoles; Indomethacin; Male; Mice; Mice, Inbred C57BL; Piperazines; Pyrimidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Species Specificity; Stomach Ulcer; Thiourea