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MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes

Tropical theileriosis is a lymphoproliferative disease caused by the intracellular schizonts of Theileria annulata, an apicomplexan parasite. It causes severe infection in cattle and the untreated cattle would possibly die within 3–4 weeks of infection. The chemotherapy for this disease is largely d...

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Autores principales: Araveti, Prasanna Babu, Vijay, Macha, Kar, Prajna Parimita, Varunan, Shalu, Srivastava, Anand
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761611/
https://www.ncbi.nlm.nih.gov/pubmed/35032948
http://dx.doi.org/10.1016/j.ijpddr.2021.12.003
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author Araveti, Prasanna Babu
Vijay, Macha
Kar, Prajna Parimita
Varunan, Shalu
Srivastava, Anand
author_facet Araveti, Prasanna Babu
Vijay, Macha
Kar, Prajna Parimita
Varunan, Shalu
Srivastava, Anand
author_sort Araveti, Prasanna Babu
collection PubMed
description Tropical theileriosis is a lymphoproliferative disease caused by the intracellular schizonts of Theileria annulata, an apicomplexan parasite. It causes severe infection in cattle and the untreated cattle would possibly die within 3–4 weeks of infection. The chemotherapy for this disease is largely dependent on the use of hydroxynaphthoquinone, namely buparvaquone. There have been reports recently of the development of resistance against this drug in T. annulata. Hence, identification of new drug molecule(s) or repurposing of existing drug molecule(s) against T. annulata is quite important. Here, we present the screening of 400 compounds included in the open-access Pathogen box from Medicine for Malaria Venture (MMV) to discover the novel compounds with potential inhibitory activity against T. annulata infected bovine leucocytes. We identified two compounds, MMV000062 and MMV560185, with IC(50) values of 2.97 μM and 3.07 μM, respectively. MMV000062 and MMV560185 were found non-toxic to BoMac cells with CC(50) values 34 μM and > 100 μM, respectively. The therapeutic indices of these compounds, MMV000062 and MMV560185, were calculated as more than 33 and 11, respectively. Further, it was observed that the parasite-infected cells under long-term culture were unable to recover with these compounds. We further deciphered that MMV560185 kills the infected cell by activation of TNFR-1 mediated extrinsic pathway of the apoptosis. The phenotypic characteristics of apoptosis were confirmed by Transmission Electron Microscopy. Our results suggest that it may be possible to develop MMV560185 further for chemotherapeutics of tropical theilerosis.
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spelling pubmed-87616112022-01-20 MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes Araveti, Prasanna Babu Vijay, Macha Kar, Prajna Parimita Varunan, Shalu Srivastava, Anand Int J Parasitol Drugs Drug Resist Regular article Tropical theileriosis is a lymphoproliferative disease caused by the intracellular schizonts of Theileria annulata, an apicomplexan parasite. It causes severe infection in cattle and the untreated cattle would possibly die within 3–4 weeks of infection. The chemotherapy for this disease is largely dependent on the use of hydroxynaphthoquinone, namely buparvaquone. There have been reports recently of the development of resistance against this drug in T. annulata. Hence, identification of new drug molecule(s) or repurposing of existing drug molecule(s) against T. annulata is quite important. Here, we present the screening of 400 compounds included in the open-access Pathogen box from Medicine for Malaria Venture (MMV) to discover the novel compounds with potential inhibitory activity against T. annulata infected bovine leucocytes. We identified two compounds, MMV000062 and MMV560185, with IC(50) values of 2.97 μM and 3.07 μM, respectively. MMV000062 and MMV560185 were found non-toxic to BoMac cells with CC(50) values 34 μM and > 100 μM, respectively. The therapeutic indices of these compounds, MMV000062 and MMV560185, were calculated as more than 33 and 11, respectively. Further, it was observed that the parasite-infected cells under long-term culture were unable to recover with these compounds. We further deciphered that MMV560185 kills the infected cell by activation of TNFR-1 mediated extrinsic pathway of the apoptosis. The phenotypic characteristics of apoptosis were confirmed by Transmission Electron Microscopy. Our results suggest that it may be possible to develop MMV560185 further for chemotherapeutics of tropical theilerosis. Elsevier 2022-01-04 /pmc/articles/PMC8761611/ /pubmed/35032948 http://dx.doi.org/10.1016/j.ijpddr.2021.12.003 Text en © 2022 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular article
Araveti, Prasanna Babu
Vijay, Macha
Kar, Prajna Parimita
Varunan, Shalu
Srivastava, Anand
MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title_full MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title_fullStr MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title_full_unstemmed MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title_short MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
title_sort mmv560185 from pathogen box induces extrinsic pathway of apoptosis in theileria annulata infected bovine leucocytes
topic Regular article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761611/
https://www.ncbi.nlm.nih.gov/pubmed/35032948
http://dx.doi.org/10.1016/j.ijpddr.2021.12.003
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