Key Points
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Although malaria continues to affect 40% of the world's population and is estimated to be responsible for up to 1 million deaths per year, the number of cases reported by the World Health Organization has declined.
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Some fear that these advances will be reversed if parasites become resistant to artemisinins, which is currently the only class of antimalarial drug that works effectively against all drug-resistant parasite strains. Ever-slowing response times to artemisinin monotherapies and the risk that these compounds will lose effectiveness over time has spurred the new search for replacement therapies.
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The World Health Organization and several non-profit, non-governmental organizations have made the elimination of malaria a long-term public health goal. This has generated interest in developing novel antimalarial compounds that can not only eliminate the symptoms of malaria but also remove all parasites from the body and prevent the spread of malaria.
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In recent years, sophisticated and powerful cellular and phenotypic screening methods have identified drug candidates that are active against different stages of the parasite's life cycle, and at least two of these novel classes of antimalarial drugs are being tested for efficacy in humans.
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For known, validated antimalarial 'targets', structure-guided drug design has yielded drug candidates that have higher potency and activity against drug-resistant malaria parasites than the drugs that are currently available against these targets.
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Insightful chemical design has also resulted in new drug candidates that have improved potency or that remain in the patient's bloodstream for a longer period of time.
Abstract
Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public–private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite life cycle. In this Review, we discuss the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing.
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Change history
02 December 2013
In the above article, reference 69 was cited incorrectly at the end of the sentence “these compounds have been resynthesized and this ‘malaria box’ of potential chemical starting points can be obtained from the Medicines for Malaria Venture (MMV)” and this superfluous citation has now been deleted online. Also, two of the structures shown in Figure 3 (GNF156 and DSM265) contained errors. The figure has now been corrected online. We apologize to the authors and to readers for any misunderstanding caused.
24 July 2017
In the above article, the structure of DSM265 in figure 3 was missing a methyl group. This has now been corrected in the PDF and online. We apologize to readers for any confusion caused.
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Acknowledgements
E.A.W and E.L.F acknowledge support from US National Institutes of Health grants R01 AI090141 and F32AI102567, respectively. All authors also gratefully acknowledge support from the Bill and Melinda Gates Foundation (grant OPP1054480) and the Medicines for Malaria Venture.
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E.A.W. holds a research grant from the Wellcome Trust which is shared with the Novartis Institute for Tropical Diseases, Singapore, as the primary recipient. A.K.C. is an author on patents for compounds described in this manuscript. E.L.F. declares no competing interests.
Glossary
- Elimination
-
An absence of the local transmission of malaria.
- Eradication
-
The complete removal of malaria parasites so that there is no transmission worldwide.
- Radical cure
-
A treatment that eliminates the hypnozoite form of the parasite and thus prevents relapse from Plasmodium vivax or Plasmodium ovale infections.
- Hypnozoites
-
The dormant liver-stage forms of the parasite that develop when some Plasmodium vivax and Plasmodium ovale sporozoites invade hepatocytes. These hypnozoites do not replicate but can become activated weeks, months or years later, resulting in a blood-stage infection.
- Single exposure, radical cure and prophylaxis (SERCaP).
-
A treatment that would only need to be administered in one dose and that would eliminate blood-stage parasites (alleviating the symptoms of malaria) and kill hypnozoites (preventing a new infection from developing).
- Target product profile
-
A set of guidelines that describes the ideal product. For antimalarial drugs, it might include pharmacokinetic and pharmocodynamic parameters, oral bioavailability, cost, potency and activity against different life cycle stages.
- Scaffold
-
The fixed part of a lead molecule on which chemical functional groups are substituted or exchanged.
- Cheminformatic analysis
-
Computational analysis using systematic or common chemical names; used to group scaffold families and to discover known activities, toxicities and sometimes targets.
- Structure–activity relationships
-
(SARs). The relationships between the chemical structures of molecules and their biological activities. The analysis of SARs allows scientists to identify the chemical groups that are responsible for a compound's biological activity.
- Lead compound
-
This is a chemical compound often discovered in a screen that has pharmacological or biological activity. Its chemical structure is used as a starting point for chemical modifications that improve potency, selectivity or pharmacokinetic parameters.
- Merozoites
-
The infectious parasites that are released when blood-stage schizonts rupture. The merozoites can bind to and invade erythrocytes in a matter of seconds.
- Enantiomers
-
Molecules that are structurally equivalent but are mirror images of one another and therefore not superimposable. It is common for one enantiomer of a drug to have more activity than the other.
- Standard membrane-feeding assay
-
An assay used to determine if a blood culture contains gametocytes that are infectious to mosquitoes. In the assay, mosquitoes feed on human blood that is infected with Plasmodium falciparum parasites and covered with parafilm.
- Causal prophylaxis
-
The prevention of a blood-stage infection by a therapeutic compound that prevents sporozoites from invading or developing within the liver.
- Ookinetes
-
The motile parasite forms that develop from zygotes. Ookinetes are tetraploid as a result of meiosis in the zygote and develop into oocysts on the midgut wall.
- High-content imaging
-
Automated microscopy that collects images of cellular monolayers stained with antibodies. Computer algorithms are then used to automatically identify features such as number of cells, number of cells in mitosis, size of cells or aberrant shape.
- Gametocytes
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The sexual stages of parasites that develop from asexual parasites and that differentiate into gametes in the mosquito. They are thus the parasite forms responsible for transmission.
- Sporozoites
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The motile infectious forms of the parasite that are transmitted from the mosquito to the human, where they migrate from the dermis to a blood vessel and eventually invade a liver cell.
- Schizont
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A malaria parasite that has completed the process of DNA replication and syncytial nuclear division but that is still contained within a single red blood cell or hepatocyte.
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Flannery, E., Chatterjee, A. & Winzeler, E. Antimalarial drug discovery — approaches and progress towards new medicines. Nat Rev Microbiol 11, 849–862 (2013). https://doi.org/10.1038/nrmicro3138
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DOI: https://doi.org/10.1038/nrmicro3138
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