In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates

We report the results of a screen of a library of 925 potential prenyl synthase inhibitors against T. brucei farnesyl diphosphate synthase (TbFPPS) and against Trypanosoma 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 sub-micromolar 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, finding survival increased by up to 16 days. We also investigated the binding of three lipophilic bisphosphonates to an expressed TbFPPS using crystallography, as well as investigating thermodynamics of binding using isothermal titration calorimetry.