imidocarb-dipropionate 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

It was found that surprisingly low doses of four babesicides were effective against Babesia divergens in gerbils and it was concluded that this was due to the involvement of host resistance, which may be of a non-specific nature. The efficacy of the drugs relative to each other was the same in gerbils as in cattle and this host-parasite system is evidently more suitable for the screening of babesicides than are other rodent babesia systems. The prophylactic dose of imidocarb dipropionate required to provide a similar degree of protection in gerbils as in cattle was found to be much higher and was very close to toxic levels. Challenge infections resulted in sterile immunity. Acute babesiosis in gerbils could be cured with all four drugs if parasitaemias were below approximately 45 per cent and packed cell volumes above 18 per cent at treatment.

Topics: Animals; Antiprotozoal Agents; Babesiosis; Carbanilides; Diminazene; Disease Models, Animal; Female; Gerbillinae; Imidocarb; Male; Quinolinium Compounds; Urea