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Publication Abstract from PubMed

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 approximately 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.

In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates.,Yang G, Zhu W, Kim K, Byun SY, Choi G, Wang K, Cha JS, Cho HS, Oldfield E, No JH Antimicrob Agents Chemother. 2015 Dec;59(12):7530-9. doi: 10.1128/AAC.01873-15., Epub 2015 Sep 21. PMID:26392508^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.