tosylarginine-methyl-ester 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 cause of death in bacteremia due to Streptococcus pneumoniae remains unclear. The role of intravascular coagulation and splenectomy was investigated in rabbits with lethal pneumococcal bacteremia. The staphylococcal clumping titer in serum, a measure of fibrin degradation products, increased early and persisted until death. This titer correlated with the level of bacteremia. The partial thromboplastin time and platelet-rich plasma clotting time also increased as the disease worsened. However, the prothrombin time remained normal. 125I-labeled fibrinogen was cleared normally from the plasma of infected rabbits, whether intact or splenectomized. Similarly, the concentration of fibrogen in plasma remained normal, even though the level of fibrin degradation products increased, and no difference in these parameters was noted between intact and splenectomized rabbits. Fibrin deposition could not be detected in any of the organs studied. Neither the level of fibrin degradation products nor survival was affected by treatment with hydrocortisone, hexadimethrine, cytochrome c, carboxypeptidase B, epsilon-aminocaproic acid, or heparin. These data suggest that intravascular coagulation occurs in this experimental infection prior to the onset of shock but probably plays only a minor role in lethality.

Topics: Animals; Anti-Bacterial Agents; Blood Coagulation Tests; Disease Models, Animal; Disseminated Intravascular Coagulation; Esterases; Fibrinogen; Pneumococcal Infections; Rabbits; Sepsis; Splenectomy; Tosylarginine Methyl Ester