Novel inhibitors of the <i>Plasmodium falciparum</i> electron transport chain

Stocks, Paul A.; Barton, Victoria; Antoine, Thomas; Biagini, Giancarlo A.; Ward, Stephen A.; O’Neill, Paul M.

doi:10.1017/s0031182013001571

Cited by 36 publications

(19 citation statements)

References 68 publications

(103 reference statements)

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“…Notwithstanding, today within the MMV portfolio there are compounds whose activity was aimed at specific targets including dihydroorotate dehydrogenase (Booker et al 2010). The electron transport chain, essential in Plasmodium pyrimidine biosynthesis, has also been targeted with potent quinolone-based compounds (Stocks et al 2013). Developing more sophisticated modelling methods continues to contribute towards lead compound identification and refinement against specific targets but also increasing the use of physicochemical constraints to enhance the probability of compounds emerging with drug-like features (Cunningham et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Emerging paradigms in anti-infective drug design

Barrett

Croft

2014

Parasitology

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The need for new drugs to treat microbial infections is pressing. The great progress made in the middle part of the twentieth Century was followed by a period of relative inactivity as the medical needs relating to infectious disease in the wealthier nations receded. Growing realisation that anti-infectives are needed in many parts of the world, to treat neglected diseases as well as to combat the burgeoning risk of resistance to existing drugs, has galvanised a new wave of research into anti-microbial drugs. The transfer of knowledge from the Pharmaceutical industry relating to the importance of understanding how to target drugs successfully within the body, and improved understanding of how pathogens interact with their hosts, is driving a series of new paradigms in anti-infective drug design. Here we provide an overview of those processes as an introduction to a series of articles from experts in this area that emerged from a meeting entitled “Emerging Paradigms in Anti-Infective Drug Design” held in London on the 17th and 18th September 2012. The symposium was organised jointly by British Society for Parasitology (BSP) and the Biological & Medicinal Chemistry sector of the Royal Society of Chemistry (RSC) and held at the London School of Hygiene & Tropical Medicine. The symposium set out to cover all aspects of the identification of new therapeutic modalities for the treatment of neglected and tropical diseases. We aimed to bring together leading scientists from all the disciplines working in this field and cover the pharmacology, medicinal chemistry and drug delivery of potential new medicines. Sessions were held on: “Target diseases and targets for drugs”, “Target based medicinal chemistry”, “Bioavailability and chemistry”, “Targeting intracellular microbes”, “Alternative approaches and models”, and “New anti-infectives – how do we get there?”This symposium was organised by Simon Croft (LSHTM) and Mike Barrett (University of Glasgow) for the BSP, and David Alker (David Alker Associates) and Andrew Stachulski (University of Liverpool) for the Biological & Medicinal Chemistry sector of the RSC.

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Section: Introductionmentioning

confidence: 99%

Emerging paradigms in anti-infective drug design

Barrett

Croft

2014

Parasitology

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“…Inhibition at either site is sufficient to block the catalytic cycle of cyt bc 1 (Q cycle), which ultimately leads to pyrimidine starvation and cell death in P. falciparum (4,5). To date, pyridones (6,7), naphthoquinones (8,9), acridones (10), quinolones (11)(12)(13), and benzene sulfonamides (14) have been identified as potent inhibitors of Plasmodium cyt bc 1 (15). This includes atovaquone (ATV), which targets the Q o site of the P. falciparum cytochrome bc 1 complex (16).…”

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confidence: 99%

Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc ₁ Complex of Plasmodium falciparum

Stickles

Almeida

Morrisey

et al. 2015

Antimicrob Agents Chemother

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fThe cytochrome bc 1 complex (cyt bc 1 ) is the third component of the mitochondrial electron transport chain and is the target of several potent antimalarial compounds, including the naphthoquinone atovaquone (ATV) and the 4(1H)-quinolone ELQ-300. Mechanistically, cyt bc 1 facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Q o ) and reductive (Q i ) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Q o site, it has been challenging to design selective Q i site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc 1 . Here, we used the proposed Q i site inhibitor ELQ-300 to generate a drug-resistant Plasmodium falciparum clone containing an I22L mutation at the Q i region of cyt b. Using this D1 clone and the Y268S Q o mutant strain, P. falciparum Tm90-C2B, we created a structureactivity map of Q i versus Q o site selectivity for a series of endochin-like 4(1H)-quinolones (ELQs). We found that Q i site inhibition was associated with compounds containing 6-position halogens or aryl 3-position side chains, while Q o site inhibition was favored by 5,7-dihalogen groups or 7-position substituents. In addition to identifying ELQ-300 as a preferential Q i site inhibitor, our data suggest that the 4(1H)-quinolone scaffold is compatible with binding to either site of cyt bc 1 and that minor chemical changes can influence Q o or Q i site inhibition by the ELQs. Malaria is a devastating parasitic disease that affects Ͼ200 million people every year and is a leading cause of mortality in the developing world (1). Malaria is caused by Plasmodium parasites, which are transmitted by the bites of infected Anopheles mosquitoes and progress through a series of biologically distinct stages within the hepatocytes and red blood cells of the human host. The most lethal malarial parasite, Plasmodium falciparum, has developed resistance to many frontline antimalarials, including the quinolines quinine, chloroquine, and mefloquine, as well as the antifolates pyrimethamine and sulfadoxine. In many regions of the world, the treatment of multidrug-resistant malaria relies on the use of artemisinin-based combination therapies (ACTs), such as artesunate-amodiaquine and dihydroartemisinin-piperaquine. Unfortunately, artemisinin resistance has emerged in regions of Southeast Asia (2), which threatens to derail the ACT treatment strategy and further restrict therapeutic options for patients in malarious regions. As a result, there is a pressing need for new antimalarial compounds, particularly those that effectively inhibit drug-resistant parasites and function throughout multiple stages of the parasite life cycle to provide combined treatment, prophylaxis, and transmission-blocking activity against malaria (3).Complex III of the mitochondrial electron transport chain, also known as the cytochrome bc 1 co...

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“…suggests that many of the drugs used in the treatment of poultry coccidiosis may be effective against C. cayetanensis infection (Tang et al, 2015). Drugs affecting the mitochondrial and apicoplast metabolism could be developed and evaluated in clinical trials to test their effectiveness for cyclosporiasis (Saremy et al, 2011;Goodman et al, 2013;Stocks et al, 2014). …”

Section: Vaccines and Drug Therapymentioning

confidence: 99%

Cyclospora cayetanensis

Chacín-Bonilla¹

2019

Water and Sanitation for the 21st Century: Health and Microbiological Aspects of Excreta and Wastewater Management (Global Wate

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Novel inhibitors of the Plasmodium falciparum electron transport chain

Cited by 36 publications

References 68 publications

Emerging paradigms in anti-infective drug design

Emerging paradigms in anti-infective drug design

Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc ₁ Complex of Plasmodium falciparum

Cyclospora cayetanensis

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Novel inhibitors of the Plasmodium falciparum electron transport chain

Cited by 36 publications

References 68 publications

Emerging paradigms in anti-infective drug design

Emerging paradigms in anti-infective drug design

Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc 1 Complex of Plasmodium falciparum

Cyclospora cayetanensis

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Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc ₁ Complex of Plasmodium falciparum