Inhibiting Plasmodium cytochrome bc1: a complex issue

Barton, Victoria; Fisher, Nicholas; Biagini, Giancarlo A.; Ward, Stephen A.; O’Neill, Paul M.

doi:10.1016/j.cbpa.2010.05.005

Cited by 108 publications

(111 citation statements)

References 30 publications

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“…Previous antimalarial projects that have focused on the development of bc 1 inhibitors have had to be terminated because of safety concerns regarding cardiotoxicity (20). Therefore we established a beef-heart bc 1 counterscreen to assess possible mitochondrial toxicity.…”

Section: Nm)mentioning

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.

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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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Section: Nm)mentioning

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.

Self Cite

145

128

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“…1.10.2.2) 10 , which is a central component of the respiratory chain and thus of cellular energy conversion 11 . As a consequence, atovaquone collapses the mitochondrial membrane potential and blocks energy supply of the parasites [12][13][14][15] . The drug may also act via blocking the essential pyrimidine biosynthesis, as a recent study indicates that the main metabolic function of cyt bc 1 activity in Plasmodium falciparum appears to be the regeneration of ubiquinone, which is the substrate of dihydroorotate dehydrogenase, the essential enzyme for this biosynthetic pathway 6,13 .…”

mentioning

confidence: 99%

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

2014

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“…Several mutations, giving rise to atovaquone-resistant strains of P. falciparum and Toxoplasma gondii, have been reported since the turn of the century (23)(24)(25)(26)(27). These mutations arise in the Q o pocket and prevent atovaquone from binding (28).…”

mentioning

confidence: 99%

“…A recent X-ray structure of cytochrome bc 1 from Saccharomyces cerevisiae has shown atovaquone bound in the catalytic Q o site, offering explanation for the cross-species resistance (20). Many different classes of compound have been investigated as potential drugs and much work has focused on inhibition of the Q o site (23,(29)(30)(31)(32). The 4(1H)-pyridones have been researched for their antimalarial properties since the 1960s, based on the compound clopidol (33,34) (Fig.…”

mentioning

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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Inhibiting Plasmodium cytochrome bc1: a complex issue

Cited by 108 publications

References 30 publications

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

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

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

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

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Inhibiting Plasmodium cytochrome bc1: a complex issue

Cited by 108 publications

References 30 publications

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

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

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

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

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