birt-377 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

Both preclinical and clinical data have identified leukocyte function-associated antigen-1 (LFA-1) as an important component of inflammatory disease states. We evaluated small molecule inhibitors of this glycoprotein in several animal models in which the inflammatory process is dependent on human or non-human primate LFA-1. (R)-5(4-bromobenzyl)-3(3,5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dione, BIRT 377, effectively suppressed the production of human immunoglobulin (IgG) following reconstitution of severe combined immunodeficient (SCID) mice with human peripheral blood mononuclear cells. The BIRT 377 analog, BIX 642, inhibited the cellular infiltrate and increase in skin thickness associated with the delayed-type hypersensitivity reaction in previously immunized squirrel monkeys challenged with antigen. BIX 642 also inhibited the trans-vivo delayed-type hypersensitivity response in the footpads of SCID mice injected with human peripheral blood mononuclear cells and donor-sensitive antigen. These results demonstrate the efficacy of small molecule inhibitors of LFA-1 in preclinical models of inflammation dependent on human or non-human primate LFA-1.

Topics: Animals; Disease Models, Animal; Humans; Hypersensitivity, Delayed; Imidazoles; Imidazolidines; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Leukocytes, Mononuclear; Lymphocyte Function-Associated Antigen-1; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Saimiri