ipi-145 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

Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.

Topics: Animals; Asthma; Basophils; Cell Degranulation; Chalcones; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Mice; Models, Molecular; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.

Topics: Animals; Arthritis; Asthma; Collagen Type II; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Isoquinolines; Lupus Erythematosus, Systemic; Molecular Structure; Ovalbumin; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Purines; Rats; Rats, Inbred Lew; Rats, Wistar; Structure-Activity Relationship