Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs.
Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA.
Diana
D
Ortiz
Veterans Affairs Medical Center, Portland, Oregon, USA.
Isaac
I
Forquer
Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA.
Jan
J
Boitz
Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA.
Radika
R
Soysa
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA.
Carolyn
C
Elya
Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA.
Audrey
A
Fulwiler
Veterans Affairs Medical Center, Portland, Oregon, USA.
Aaron
A
Nilsen
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA.
Tamsen
T
Polley
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA Veterans Affairs Medical Center, Portland, Oregon, USA.
Michael K
MK
Riscoe
Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA.
Buddy
B
Ullman
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA landfear@ohsu.edu.
Scott M
SM
Landfear
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects / Q000378:metabolism; D007894:Leishmania mexicana / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009243:NAD / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000981:Antiprotozoal Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D009243:NAD; D000255:Adenosine Triphosphate; D014450:Electron Transport Complex III