An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method
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-appr...
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2017
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v132_n_p249_LaraRamirez http://hdl.handle.net/20.500.12110/paper_02235234_v132_n_p249_LaraRamirez |
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paper:paper_02235234_v132_n_p249_LaraRamirez2023-06-08T15:21:42Z An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method Agustí, Rosalía Uhrig, María Laura Docking Drug repositioning FDA-drugs Trans-sialidase Trypanosoma cruzi anabolic agent antibiotic agent antihistaminic agent antihypertensive agent azlocillin cardiac glycoside cefonicid cefoperazone cefsulodin cromoglycate disodium dicoumarol doxazosin mesylate flubendazole ketanserin raloxifene salazosulfapyridine sialidase inhibitor telmisartan terfenadine troglitazone ziprasidone antiinflammatory agent antiprotozoal agent glycoprotein salazosulfapyridine sialidase trans-sialidase anion exchange chromatography antihypertensive activity antimicrobial activity Article chemical structure controlled study drug repositioning drug screening enzymatic assay enzyme inhibition enzyme mechanism food and drug administration in vitro study in vivo study nonhuman sialylation Trypanosoma cruzi animal antagonists and inhibitors chemistry drug effects drug repositioning mouse procedures structure activity relation Trypanosoma cruzi Animals Anti-Inflammatory Agents Antiprotozoal Agents Drug Repositioning Glycoproteins Mice Neuraminidase Structure-Activity Relationship Sulfasalazine Trypanosoma cruzi 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. © 2017 Fil:Agusti, R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Uhrig, M.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v132_n_p249_LaraRamirez http://hdl.handle.net/20.500.12110/paper_02235234_v132_n_p249_LaraRamirez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Docking Drug repositioning FDA-drugs Trans-sialidase Trypanosoma cruzi anabolic agent antibiotic agent antihistaminic agent antihypertensive agent azlocillin cardiac glycoside cefonicid cefoperazone cefsulodin cromoglycate disodium dicoumarol doxazosin mesylate flubendazole ketanserin raloxifene salazosulfapyridine sialidase inhibitor telmisartan terfenadine troglitazone ziprasidone antiinflammatory agent antiprotozoal agent glycoprotein salazosulfapyridine sialidase trans-sialidase anion exchange chromatography antihypertensive activity antimicrobial activity Article chemical structure controlled study drug repositioning drug screening enzymatic assay enzyme inhibition enzyme mechanism food and drug administration in vitro study in vivo study nonhuman sialylation Trypanosoma cruzi animal antagonists and inhibitors chemistry drug effects drug repositioning mouse procedures structure activity relation Trypanosoma cruzi Animals Anti-Inflammatory Agents Antiprotozoal Agents Drug Repositioning Glycoproteins Mice Neuraminidase Structure-Activity Relationship Sulfasalazine Trypanosoma cruzi |
| spellingShingle |
Docking Drug repositioning FDA-drugs Trans-sialidase Trypanosoma cruzi anabolic agent antibiotic agent antihistaminic agent antihypertensive agent azlocillin cardiac glycoside cefonicid cefoperazone cefsulodin cromoglycate disodium dicoumarol doxazosin mesylate flubendazole ketanserin raloxifene salazosulfapyridine sialidase inhibitor telmisartan terfenadine troglitazone ziprasidone antiinflammatory agent antiprotozoal agent glycoprotein salazosulfapyridine sialidase trans-sialidase anion exchange chromatography antihypertensive activity antimicrobial activity Article chemical structure controlled study drug repositioning drug screening enzymatic assay enzyme inhibition enzyme mechanism food and drug administration in vitro study in vivo study nonhuman sialylation Trypanosoma cruzi animal antagonists and inhibitors chemistry drug effects drug repositioning mouse procedures structure activity relation Trypanosoma cruzi Animals Anti-Inflammatory Agents Antiprotozoal Agents Drug Repositioning Glycoproteins Mice Neuraminidase Structure-Activity Relationship Sulfasalazine Trypanosoma cruzi Agustí, Rosalía Uhrig, María Laura An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| topic_facet |
Docking Drug repositioning FDA-drugs Trans-sialidase Trypanosoma cruzi anabolic agent antibiotic agent antihistaminic agent antihypertensive agent azlocillin cardiac glycoside cefonicid cefoperazone cefsulodin cromoglycate disodium dicoumarol doxazosin mesylate flubendazole ketanserin raloxifene salazosulfapyridine sialidase inhibitor telmisartan terfenadine troglitazone ziprasidone antiinflammatory agent antiprotozoal agent glycoprotein salazosulfapyridine sialidase trans-sialidase anion exchange chromatography antihypertensive activity antimicrobial activity Article chemical structure controlled study drug repositioning drug screening enzymatic assay enzyme inhibition enzyme mechanism food and drug administration in vitro study in vivo study nonhuman sialylation Trypanosoma cruzi animal antagonists and inhibitors chemistry drug effects drug repositioning mouse procedures structure activity relation Trypanosoma cruzi Animals Anti-Inflammatory Agents Antiprotozoal Agents Drug Repositioning Glycoproteins Mice Neuraminidase Structure-Activity Relationship Sulfasalazine Trypanosoma cruzi |
| description |
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. © 2017 |
| author |
Agustí, Rosalía Uhrig, María Laura |
| author_facet |
Agustí, Rosalía Uhrig, María Laura |
| author_sort |
Agustí, Rosalía |
| title |
An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| title_short |
An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| title_full |
An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| title_fullStr |
An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| title_full_unstemmed |
An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method |
| title_sort |
in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of trypanosoma cruzi predicted by a computational drug repositioning method |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02235234_v132_n_p249_LaraRamirez http://hdl.handle.net/20.500.12110/paper_02235234_v132_n_p249_LaraRamirez |
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