Probing binding determinants in center P of the cytochrome bc(1) complex using novel hydroxy-naphthoquinones.
Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc(1) complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc(1) complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc(1) complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic.
Hughes
Louise M
LM
Department of Biochemistry, Dartmouth Medical School, 7200 Vail, Hanover, NH 03755, USA.
Covian
Raul
R
Gribble
Gordon W
GW
Trumpower
Bernard L
BL
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000627:therapeutic use; D053626:Atovaquone / Q000737:chemistry / Q000627:therapeutic use; D002417:Cattle; D045303:Cytochromes b / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008288:Malaria / Q000188:drug therapy; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D011010:Pneumocystis / Q000187:drug effects
D000962:Antimalarials; D009285:Naphthoquinones; D045303:Cytochromes b; D014450:Electron Transport Complex III; D053626:Atovaquone