TY - JOUR
T1 - An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method
AU - Lara-Ramirez, Edgar E.
AU - López-Cedillo, Julio Cesar
AU - Nogueda-Torres, Benjamin
AU - Kashif, Muhammad
AU - Garcia-Perez, Carlos
AU - Bocanegra-Garcia, Virgilio
AU - Agusti, Rosalía
AU - Uhrig, María Laura
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2017
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Docking
KW - Drug repositioning
KW - FDA-drugs
KW - Trans-sialidase
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85016308619&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.03.063
DO - 10.1016/j.ejmech.2017.03.063
M3 - Artículo
C2 - 28364659
SN - 0223-5234
VL - 132
SP - 249
EP - 261
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -