Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration.
African trypanosomiasis is a deadly disease for which few chemotherapeutic options are available. The causative agents, Trypanosoma brucei rhodesiense and T. b. gambiense, utilize a non-cytochrome, alternative oxidase (AOX) for their cellular respiration. The absence of this enzyme in mammalian cells makes it a logical target for therapeutic agents. We designed three novel compounds, ACB41, ACD15, and ACD16, and investigated their effects on trypanosome alternative oxidase (TAO) enzymatic activity, parasite respiration, and parasite growth in vitro. All three compounds contain a 2-hydroxybenzoic acid moiety, analogous to that present in SHAM, and a prenyl side chain similar to that found in ubiquinol. ACD15 and ACD16 are further differentiated by the presence of a solubility-enhancing carbohydrate moiety. Kinetic studies with purified TAO show that all three compounds competitively inhibit TAO, and two compounds, ACB41 and ACD15, have inhibition constants five- and three-fold more potent than SHAM, respectively. All three compounds inhibited the respiration and growth of continuously cultured T. b. brucei bloodstream cells in a dose-dependent manner. None of the compounds interfered with respiration of rat liver mitochondria, nor did they inhibit the growth of a continuously cultured mammalian cell line. Collectively, the results suggest we have identified a new class of compounds that are inhibitors of TAO, have trypanocidal properties in vitro, and warrant further investigation in vivo.
Ott
Robert
R
Vanderbilt University School of Medicine, Department of Microbiology and Immunology, Nashville, TN 37232, United States.
Chibale
Kelly
K
Anderson
Sedrick
S
Chipeleme
Alex
A
Chaudhuri
Minu
M
Guerrah
Abdelmadjid
A
Colowick
Nancy
N
Hill
George C
GC
D000818:Animals; D002241:Carbohydrates; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D024101:Mitochondrial Proteins; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010940:Plant Proteins; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D012457:Salicylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020156:Salicylic Acid; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D000099188:Alternative Oxidase
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D005960:Glucosides; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D015800:Protozoan Proteins; D012457:Salicylamides; D012459:Salicylates; D020156:Salicylic Acid; D014344:Trypanocidal Agents; D000099188:Alternative Oxidase; C519919:ACB 41; C519917:ACD 15; C519918:ACD 16