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An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method
Ist Teil von
European journal of medicinal chemistry, 2017-05, Vol.132, p.249-261
Ort / Verlag
France: Elsevier Masson SAS
Erscheinungsjahr
2017
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion-exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti-hypertensive, and antibiotic properties showed better trypanocidal effects (LC50 range = 4.5–25.8 μg/mL) than the reference drugs, nifurtimox and benznidazole (LC50 range = 36.1–46.8 μg/mL) in both strains in the in vitro model. The anti-inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors.
Sulfasalzaine as trans-sialidase inhibitor found by a computational drug repositioning protocol. [Display omitted]
•A structure-based virtual screening of 3180 FDA-approved drugs, as trans-sialidase inhibitors was performed.•Cefoperazone-sodium, terfenadine, ketanserin-tartrate and doxazosin-mesilate showed better trypanocidal effects during in vitro assays.•The anti-inflammatory sulfasalazine showed moderate (37.6%) trans-sialidase inhibition.•Sulfasalazine reduced 61% of parasitemia at 6 h during an in vivo assay.