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 ³H-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. Graphical abstract Image 1 Highlights • 17 of 796 MMV compounds inhibited proliferation of T parva infected lymphocytes. • 15 of the 17 hit compounds also inhibited proliferation of control cells. • MMV008212 and MMV688372 represent promising leads, therapeutic index >8. • Dasatinib was as active and safe as buparvaquone in vitro, therapeutic index >2000. [ABSTRACT FROM AUTHOR]