Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80)

Fry, Mitchell; Pudney, Mary

doi:10.1016/0006-2952(92)90213-3

Cited by 458 publications

(334 citation statements)

References 19 publications

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“…The effects of the drug on cell respiration and the structural similarities of atovaquone and ubiquinol suggested that the bc 1 complex was the target (4). This has been supported by the emergence of mutations in the cytochrome b gene coincident with resistance to the drug (9 -14).…”

mentioning

confidence: 99%

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Kessl

Lange

Merbitz-Zahradnik

et al. 2003

Journal of Biological Chemistry

153

163

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Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc 1 complex. We have examined the interaction of atovaquone with the bc 1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc 1 complex competitively with apparent K i ‫؍‬ 9 nM, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc 1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc 1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc 1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc 1 complex (K i ‫؍‬ 80 nM) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (K i ‫؍‬ 100 nM) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc 1 complex and explain the differential inhibition of the fungal versus mammalian enzymes.

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confidence: 99%

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Kessl

Lange

Merbitz-Zahradnik

et al. 2003

Journal of Biological Chemistry

153

163

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“…Atovaquone, a hydroxynapthoquinone ( Fig. 1), binds cytochrome bc 1 at the Q o site (20,21). It is used as a fixed-dose combination with proguanil (marketed as Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers.…”

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confidence: 99%

Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Capper

O’Neill

Fisher

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome bc 1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Q o site (one of two potential binding sites within cytochrome bc 1 ) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc 1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Q o site but bind at the Q i site. The discovery that these compounds bind at the Q i site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Q i also explains the ability of this class to overcome parasite Q o -based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles. malaria | cytochrome bc 1 | drug discovery | Plasmodium falciparum | membrane protein

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“…A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc 1 . Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position.…”

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confidence: 99%

Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

Biagini

Fisher

Shone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

145

128

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There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc 1 . Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.T he discovery of atovaquone 20 years ago validated the malaria parasite's mitochondrial electron transport chain (ETC) as an exploitable drug target. Atovaquone targets the ETC at the level of the bc 1 complex (1), with inhibition preventing proton pumping, resulting in a loss of mitochondrial membrane potential (2) and eventual organelle dysfunction, an important function of which is to provide intermediates for pyrimidine synthesis (3, 4). The bc 1 complex requires reducing equivalents provided by ubiquinol, which in turn is generated by membrane-bound dehydrogenases upstream in the ETC that catalyze redox reactions by reducing ubiquinone. The parasite lacks the canonical protonmotive NADH dehydrogenase (Complex I) but instead harbors a bacterial-like type II NADH:ubiquinone oxidoreductase, Plasmodium falciparum NDH2 (PfNDH2) (5). Based on these key observations, we undertook a drug-discovery initiative to develop costeffective inhibitors capable of inhibiting PfNDH2 with the goal of providing antimalarials that overcome the limitations of the expensive atovaquone. Although our initial drug-discovery efforts were focused on optimization of activity versus PfNDH2, we found, during hit-to-lead development, that optimized structures with single-digit nanomolar activity versus the primary target ...

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Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80)

Cited by 458 publications

References 19 publications

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁

Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

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Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80)

Cited by 458 publications

References 19 publications

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

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Antimalarial 4(1H)-pyridones bind to the Q _i site of cytochrome bc ₁