2-5-dimethylcelecoxib 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

We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3) and prolonged the lifespan of heart failure mice with genetic dilated cardiomyopathy or transverse aortic constriction-induced left ventricular hypertrophy. However, it remained unclear how DM-celecoxib regulated structure and function of cardiomyocytes and cardiac fibroblasts involved in cardiac remodeling. In the present study, therefore, we investigated the effect of DM-celecoxib on isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation, because DM-celecoxib prevented isoprenaline-induced cardiac remodeling in vivo. DM-celecoxib suppressed isoprenaline-induced neonatal rat cardiomyocyte hypertrophy by the inhibition of Akt phosphorylation resulting in the activation of GSK-3 and the inhibition of β-catenin and mammalian target of rapamycin (mTOR). DM-celecoxib also suppressed the proliferation and the production of matrix metalloproteinase-2 and fibronectin of rat cardiac fibroblasts. Moreover, we found that phosphatase and tensin homolog on chromosome 10 (PTEN) could be a molecule to mediate the effect of DM-celecoxib on Akt. These results suggest that DM-celecoxib directly improves the structure and function of cardiomyocytes and cardiac fibroblasts and that this compound could be clinically useful for the treatment of β-adrenergic receptor-mediated maladaptive cardiac remodeling.

Topics: Animals; Animals, Newborn; Cardiomegaly; Disease Models, Animal; Fibroblasts; Glycogen Synthase Kinase 3; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Ventricular Remodeling

Topics: Animals; Cardiomegaly; Cardiomyopathy, Dilated; Disease Models, Animal; Glycogen Synthase Kinase 3; Heart Ventricles; Matrix Metalloproteinase 2; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Pyrazoles; Sulfonamides; Ventricular Remodeling

Celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug, has been shown to inhibit Akt and prevent cardiac remodeling in aortic banding-induced failing heart in mice. However, it may be difficult to use celecoxib for the treatment of heart failure because of thromboembolic adverse reactions. Since 2,5-dimethyl (DM)-celecoxib, a derivative unable to inhibit COX-2, has been also reported to inhibit Akt, we attempted to examine whether DM-celecoxib retains the ability to prevent cardiac remodeling and improve cardiac functions using a mouse model of inherited dilated cardiomyopathy (DCM). DM-celecoxib as well as celecoxib administered daily for 4 weeks inhibited Akt and subsequent phosphorylation of glycogen synthase kinase-3β and mammalian target of rapamycin. Furthermore, both celecoxib and DM-celecoxib inhibited the activities of nuclear factor of activated T cell and β-catenin and the expression of TCF7L2 (T-cell-specific transcriptional factor-7L2) and c-Myc, downstream mediators related to cardiac hypertrophy. Functional and morphological measurements showed that these compounds improved left ventricular systolic functions (ejection fraction: vehicle, 34.7 ± 3.9%; 100 mg/kg celecoxib, 50.3 ± 1.1%, p < 0.01; 100 mg/kg DM-celecoxib, 49.8 ± 0.8%, p < 0.01), which was also evidenced by the decrease in β-myosin heavy chain and B-type natriuretic peptide, and prevented hypertrophic cardiac remodeling (heart/body weight ratio: vehicle, 10.4 ± 0.7 mg/g; 100 mg/kg celecoxib, 8.0 ± 0.3 mg/g, p < 0.01; 100 mg/kg DM-celecoxib, 8.2 ± 0.1 mg/g, p < 0.05). As a consequence, both compounds improved the survival rate (vehicle, 45%; 100 mg/kg celecoxib, 75%, p < 0.05; 100 mg/kg DM-celecoxib, 70%, p < 0.05). These results suggested that not only celecoxib but also DM-celecoxib prevents cardiac remodeling and reduces mortality in DCM through a COX-2-independent mechanism involving Akt and its downstream mediators.

Topics: Animals; Cardiomyopathy, Dilated; Celecoxib; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Knock-In Techniques; Mice; Proto-Oncogene Proteins c-akt; Pyrazoles; Signal Transduction; Sulfonamides; Ventricular Remodeling