HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome
            <i>bc</i>
            <sub>1</sub>
            Complex

Vallières, Cindy; Fisher, Nicholas; Antoine, Thomas; Al-Helal, Mohammed; Stocks, Paul A.; Berry, Neil G.; Lawrenson, Alexandre S.; Ward, Stephen A.; O’Neill, Paul M.; Biagini, Giancarlo A.; Meunier, Brigitte

doi:10.1128/aac.00486-12

Cited by 57 publications

(58 citation statements)

References 50 publications

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“…This modeling observation is consistent with our recent studies on the quinolone 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ) in yeast models (41). Introduction of point mutations into the Q i site, namely G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition; by contrast, known inhibitor resistance mutations at the Q o site did not cause HDQ resistance.…”

Section: Discussionsupporting

confidence: 80%

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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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Section: Discussionsupporting

confidence: 80%

“…Several compounds have been suggested to bind the Q i site, including potential antimalarial compounds, but due to lack of structural information have not been pursued vigorously (41). Here we provide the structure of bovine heart cytochrome bc 1 complex with 4(1H)-pyridone compounds, GW844520 and GSK932121.…”

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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“…ELQ-316-resistant clones of T. gondii were isolated following mutagenesis with N-nitroso-N-ethylurea (ENU) and subsequent exposure to ELQ-316. T. gondii strain RH Δuprt was used for the selection of ELQresistant (ER) clones after attempts to isolate T. gondii organisms with sustained ELQ resistance proved unsuccessful, similar to reports of the selection of T. gondii clones resistant to the apicomplexan inhibitor 1-hydroxy-2-dodecyl-4(1H) quinolone (HDQ) (15,16). T. gondii organisms from the flasks containing 150 nM and 200 nM ELQ-316 were found to have an increased 50% effective concentration (EC 50 ) against ELQ-316 compared to that of the parental strain.…”

Section: Resultsmentioning

confidence: 99%

“…2). The Thr222-Pro substitution is located in the Q i site of Cytb adjacent to the highly conserved Asp223 residue and is analogous to the Lys228-Met substitution in S. cerevisiae that causes resistance to the Q i site inhibitors antimycin and HDQ (16). In the context of prior evidence indicating that ELQs act at the Q i site, the association of Thr222-Pro in the Q i site with ELQ and antimycin resistance is highly suggestive that the mechanism of action of ELQ-316 is inhibition of ubiquinone reduction at the Q i site.…”

Section: Resultsmentioning

confidence: 99%

“…A Met221-Gln mutation in the S. cerevisiae cytochrome b Q i site causes resistance to ELQ-271 (12). The Lys228-Met substitution in S. cerevisiae, which is analogous to position 222 in the T. gondii cytochrome b, confers resistance to antimycin, and cocrystallization of antimycin with Bos taurus cytochrome b has shown that the analogous Lys227 forms a key bond with antimycin via a water molecule (16,19). In addition, a serine-to-tyrosine substitution at the same position in B. microti was associated with the development of ELQ-271 resistance in vivo (13).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

Alday

Bruzual

Nilsen

et al. 2017

Antimicrob Agents Chemother

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Toxoplasma gondii is an apicomplexan parasite that causes fatal and debilitating brain and eye disease. Endochinlike quinolones (ELQs) are preclinical compounds that are efficacious against apicomplexan-caused diseases, including toxoplasmosis, malaria, and babesiosis. Of the ELQs, ELQ-316 has demonstrated the greatest efficacy against acute and chronic experimental toxoplasmosis. Although genetic analyses in other organisms have highlighted the importance of the cytochrome bc 1 complex Q i site for ELQ sensitivity, the mechanism of action of ELQs against T. gondii and the specific mechanism of ELQ-316 remain unknown. Here, we describe the selection and genetic characterization of T. gondii clones resistant to ELQ-316. A T. gondii strain selected under ELQ-316 drug pressure was found to possess a Thr222-Pro amino acid substitution that confers 49-fold resistance to ELQ-316 and 19-fold resistance to antimycin, a well-characterized Q i site inhibitor. These findings provide further evidence for ELQ Q i site inhibition in T. gondii and greater insight into the interactions of Q i site inhibitors with the apicomplexan cytochrome bc 1 complex.

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The antimalarial compound ELQ‐400 is an unusual inhibitor of the bc₁ complex, targeting both Q_o and Q_i sites

et al. 2018

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Edited by Peter BrzezinskiInhibitors of the mitochondrial respiratory chain cytochrome bc 1 complex, such as the antimalarial atovaquone and ELQ-300, and many well-studied compounds, are classified as either Q o or Q i site inhibitors based on their site of action. Here, we investigated the site of action of ELQ-400 that showed an unusual behaviour, being effective against parasites resistant to the Q o site inhibitor atovaquone or to the Q i site inhibitor ELQ-300. Analysis of yeast mutants and comparison with atovaquone and other ELQs strongly suggest that ELQ-400 targets both Q o and Q i sites. Dual site inhibition would be particularly efficient as it would lower the risk of acquired resistance. However, such compounds are seldom found, which could be explained by structural and mechanistic differences between the sites.

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HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc ₁ Complex

Cited by 57 publications

References 50 publications

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

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

Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

The antimalarial compound ELQ‐400 is an unusual inhibitor of the bc₁ complex, targeting both Q_o and Q_i sites

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HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc 1 Complex

Cited by 57 publications

References 50 publications

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

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

Genetic Evidence for Cytochrome b Q i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

The antimalarial compound ELQ‐400 is an unusual inhibitor of the bc1 complex, targeting both Qo and Qi sites

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Product

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HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc ₁ Complex

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

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

Genetic Evidence for Cytochrome b Q _i Site Inhibition by 4(1 H )-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

The antimalarial compound ELQ‐400 is an unusual inhibitor of the bc₁ complex, targeting both Q_o and Q_i sites