title: Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosoma brucei soluble vacuolar pyrophosphatase.
abstract: Trypanosoma brucei, the causative agent of African trypanosomiasis, contains a soluble, vacuolar pyrophosphatase, TbVSP1, not present in humans, which is essential for the growth of bloodstream forms in their mammalian host. Here, we report the inhibition of a recombinant TbVSP1 expressed in Escherichia coli by a panel of 81 bisphosphonates. The IC50 values were found to vary from approximately 2 to 850 microM. We then used 3D QSAR (comparative molecular field and comparative molecular similarity index; CoMFA and CoMSIA) methods to analyze the enzyme inhibition results. The R2 values for the experimental versus the QSAR-predicted activities were 0.78 or 0.61 for CoMFA and 0.79 or 0.68 for CoMSIA, for two different alignments. The root-mean-square (rms) pIC50 error for the best CoMFA model was 0.41 for five test sets of five activity predictions, which translates to a factor of approximately 2.6 error in IC50 prediction. For CoMSIA, the rms pIC50 error and error factors were 0.35 and 2.2, respectively. In general, the most active compounds contained both a single aromatic ring and a hydrogen bond donor feature. Thirteen of the more potent compounds were then tested in vivo in a mouse model of T. brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kotsikorou
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Faelens
authors.forename: Zev
authors.initials: Z
authors.lastname: Tovian
authors.forename: Erin
authors.initials: E
authors.lastname: Broderick
authors.forename: Norbert
authors.initials: N
authors.lastname: Bakalara
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008958:Models, Molecular; D015800:Protozoan Proteins / Q000378:metabolism*; D011755:Pyrophosphatases / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000401:mortality; D014617:Vacuoles / Q000201:enzymology
chemical_list: D004164:Diphosphonates; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D017766:Acid Anhydride Hydrolases; D011755:Pyrophosphatases; C482344:VSP1 protein, Trypanosoma brucei; C020137:exopolyphosphatase