title: An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method.
abstract: 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 (LC50range = 4.5-25.8 μg/mL) than the reference drugs, nifurtimox and benznidazole (LC50range = 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.
authors.affiliation: Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social (IMSS), 98000 Zacatecas, Mexico.
authors.forename: Edgar E
authors.initials: EE
authors.lastname: Lara-Ramirez
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 01130 Ciudad de México, Mexico.
authors.forename: Julio Cesar
authors.initials: JC
authors.lastname: López-Cedillo
authors.affiliation: Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 01130 Ciudad de México, Mexico.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nogueda-Torres
authors.affiliation: Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa, Mexico.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Kashif
authors.affiliation: Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Perez
authors.affiliation: Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa, Mexico.
authors.forename: Virgilio
authors.initials: V
authors.lastname: Bocanegra-Garcia
authors.affiliation: Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Hidratos de Carbono (CIHIDECAR), Facultad de Ciencias Exactas y Naturales, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Agusti
authors.affiliation: Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Hidratos de Carbono (CIHIDECAR), Facultad de Ciencias Exactas y Naturales, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Uhrig
authors.affiliation: Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa, Mexico. Electronic address: gildardors@hotmail.com.
authors.forename: Gildardo
authors.initials: G
authors.lastname: Rivera
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D000981:Antiprotozoal Agents / Q000737:chemistry; D058492:Drug Repositioning / Q000379:methods*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D012460:Sulfasalazine / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000981:Antiprotozoal Agents; D006023:Glycoproteins; D012460:Sulfasalazine; C069715:trans-sialidase; D009439:Neuraminidase
keywords: Docking; Drug repositioning; FDA-drugs; Trans-sialidase; Trypanosoma cruzi