We report the results of a screen of a library of 925 potential prenyl synthase inhibitors against Trypanosoma brucei farnesyl diphosphate synthase (TbFPPS) and against T. brucei, the causative agent of human African trypanosomiasis. The most potent compounds were lipophilic analogs of the bone resorption drug zoledronate, some of which had submicromolar to low micromolar activity against bloodstream form T. brucei and selectivity indices of up to ∼300. We evaluated the effects of two such inhibitors on survival and parasitemia in a T. brucei mouse model of infection and found that survival increased by up to 16 days. We also investigated the binding of three lipophilic bisphosphonates to an expressed TbFPPS using crystallography and investigated the thermodynamics of binding using isothermal titration calorimetry.
Bibliographical noteFunding Information:
We thank the staff of beamlines 5C and 7A at the Pohang Light Source and beamline 1A at the Photon Factory for their valuable assistance. This work was supported by the U.S. Public Health Service (National Institutes of Health grant CA158191 to E.O.), a Harriet A. Harlin Professorship (E.O.), the University of Illinois Foundation/Oldfield Research Fund (E.O.), the National Research Foundation of Korea (NRF-2014K1A4A7A01074645 [J.H.N.] and NRF-2012R1A2A2A01012830 [H.-S.C.]), and a grant funded by the Korea Government Ministry of Science, Information/Communication Technology and Future Planning (MSIP), Gyeonggi-do, and the Korea Institute of Science and Technology Information (KISTI) (J.H.N.). We declare no conflicts of interest.
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)
- Infectious Diseases