title: In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates.
abstract: 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.
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea Interdisciplinary Programs of Functional Genomics, Yonsei University, Seoul, Republic of Korea.
authors.forename: Gyongseon
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kuglae
authors.initials: K
authors.lastname: Kim
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Byun
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Gahee
authors.initials: G
authors.lastname: Choi
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jeong Seok
authors.initials: JS
authors.lastname: Cha
authors.affiliation: Department of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA eoldfiel@illinois.edu joohwan.no@ip-korea.org.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.affiliation: Leishmania Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea eoldfiel@illinois.edu joohwan.no@ip-korea.org.
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
mesh_terms: D000818:Animals; D001665:Binding Sites; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018512:Parasitemia / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology / Q000473:pathology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D013816:Thermodynamics; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology / Q000473:pathology
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D051228:Geranyltranstransferase