Targeting the Cytochrome bc 1 Complex of Leishmania Parasites for Discovery of Novel Drugs
Abstract
Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc 1 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 (IC 50 s) 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 bc 1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 01, 2016
- Source ID
- 10.1128/aac.00850-16
Entities
People
- Aaron Nilsen
- Audrey Fulwiler
- Buddy Ullman
- Carolyn Elya
- Diana Ortiz
- Isaac Forquer
- Jan Boitz
- Michael K. Riscoe
- Radika Soysa
- Scott M. Landfear
- Tamsen Polley
Organizations
- National Institutes of Health
- United States Department of Defense
- United States Department of Veterans Affairs
- Veterans Affairs Medical Center (Oregon)