Leveraging the medicines for Malaria Venture malaria and pathogen boxes to discover chemical inhibitors of East Coast fever

James Nyagwange, Elias Awino, Edwin Tijhaar, Nicholas Svitek, Roger Pelle, Vishvanath Nene

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Chemotherapy of East Coast fever, a lymphoproliferative cancer-like disease of cattle causing significant economic losses in Africa, is largely dependent on the use of buparvaquone, a drug that was developed in the late 1980's. The disease is caused by the tick-borne protozoan pathogen Theileria parva. Buparvaquone can be used prophylactically and it is also active against tropical theileriosis, caused by the related parasite Theileria annulata. Recently, drug resistance was reported in T. annulata, and could occur in T. parva. Using a 3 H-thymidine incorporation assay we screened 796 open source compounds from the Medicines for Malaria Venture (MMV) to discover novel chemicals with potential inhibitory activity to T. parva. We identified nine malaria box compounds and eight pathogen box compounds that inhibited the proliferation of F100TpM, a T. parva infected lymphocyte cell line. However, only two compounds, MMV008212 and MMV688372 represent promising leads with IC 50 values of 0.78 and 0.61 μM, respectively, and CC 50 values > 5 μM. The remaining compounds exhibited a high degree of toxicity (CC 50 values < 1.09 μM) on the proliferation of bovine peripheral blood mononuclear cells stimulated with concanavalin A. We also tested the anti-cancer drug, dasatinib, used in the chemotherapy of some leukemias. Dasatinib was as active and safe as buparvaquone in vitro, with an IC 50 of 5 and 4.2 nM, respectively, and CC 50 > 10 μM. Our preliminary data suggest that it may be possible to repurpose compounds from the cancer field as well as MMV as novel anti-T. parva molecules.

LanguageEnglish
Pages80-86
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume9
DOIs
Publication statusPublished - 1 Apr 2019

Fingerprint

Theileria parva
Theileriasis
Malaria
Theileria annulata
Cattle Diseases
Drug Therapy
Neoplasms
Ticks
Concanavalin A
Drug Resistance
Pharmaceutical Preparations
Thymidine
Blood Cells
Leukemia
Parasites
Economics
Lymphocytes
Cell Line
buparvaquone

Keywords

  • Dasatinib
  • East coast fever
  • Malaria box
  • Medicines for malaria venture
  • Theileria parva

Cite this

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title = "Leveraging the medicines for Malaria Venture malaria and pathogen boxes to discover chemical inhibitors of East Coast fever",
abstract = "Chemotherapy of East Coast fever, a lymphoproliferative cancer-like disease of cattle causing significant economic losses in Africa, is largely dependent on the use of buparvaquone, a drug that was developed in the late 1980's. The disease is caused by the tick-borne protozoan pathogen Theileria parva. Buparvaquone can be used prophylactically and it is also active against tropical theileriosis, caused by the related parasite Theileria annulata. Recently, drug resistance was reported in T. annulata, and could occur in T. parva. Using a 3 H-thymidine incorporation assay we screened 796 open source compounds from the Medicines for Malaria Venture (MMV) to discover novel chemicals with potential inhibitory activity to T. parva. We identified nine malaria box compounds and eight pathogen box compounds that inhibited the proliferation of F100TpM, a T. parva infected lymphocyte cell line. However, only two compounds, MMV008212 and MMV688372 represent promising leads with IC 50 values of 0.78 and 0.61 μM, respectively, and CC 50 values > 5 μM. The remaining compounds exhibited a high degree of toxicity (CC 50 values < 1.09 μM) on the proliferation of bovine peripheral blood mononuclear cells stimulated with concanavalin A. We also tested the anti-cancer drug, dasatinib, used in the chemotherapy of some leukemias. Dasatinib was as active and safe as buparvaquone in vitro, with an IC 50 of 5 and 4.2 nM, respectively, and CC 50 > 10 μM. Our preliminary data suggest that it may be possible to repurpose compounds from the cancer field as well as MMV as novel anti-T. parva molecules.",
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Leveraging the medicines for Malaria Venture malaria and pathogen boxes to discover chemical inhibitors of East Coast fever. / Nyagwange, James; Awino, Elias; Tijhaar, Edwin; Svitek, Nicholas; Pelle, Roger; Nene, Vishvanath.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 9, 01.04.2019, p. 80-86.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Leveraging the medicines for Malaria Venture malaria and pathogen boxes to discover chemical inhibitors of East Coast fever

AU - Nyagwange, James

AU - Awino, Elias

AU - Tijhaar, Edwin

AU - Svitek, Nicholas

AU - Pelle, Roger

AU - Nene, Vishvanath

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KW - Medicines for malaria venture

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