Key Points
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Antimalarial drug discovery has substantially contributed to the gains achieved against malaria over the past two decades. However, this progress and achieving the United Nations' Millennium Goals as they relate to malaria are both being threatened by emerging drug resistance, and major gaps persist for most target compound profiles.
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Over the past decade, new, less costly and more sophisticated phenotypic screens have been developed, resulting in new drug candidates and antimalarial targets. Many of these molecules are now entering clinical development.
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Four new molecules with unprecedented modes of action are currently in Phase II trials for blood-stage treatments: KAE609 (also known as cipargamin), OZ439 (also known as artefenomel), KAF156 (also known as GNF156) and DSM265. Each of these has the potential to shorten the current 3-day regimen of artemisinin combination therapies.
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Significant contributions to the antimalarial drug discovery pipeline are being made by companies, academic institutions and non-profit organizations located in malaria-endemic countries. Moreover, Phase I studies are now being performed in populations that most need these antimalarials.
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A new translational tool has been developed whereby antimalarial pharmacodynamics is studied in subclinically infected volunteers. The model is now routinely used for evaluating new drug candidates, resulting in significant time and cost savings for development.
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Clinical efforts are needed to develop treatments for vulnerable populations such as young children and expectant mothers, and for chemoprotection. Efforts are also needed for drugs that target the liver schizont stage of malaria parasites and for preventing transmission.
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Progress has been made in early open-access drug discovery, with increased availability of proprietary compounds for screening assays.
Abstract
Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compound or product profiles, to assess progress and gaps, and to recommend priorities.
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Acknowledgements
The authors thank the MMV team for helpful discussion, as well as our partners in the many projects and the continued support of our External Scientific Advisory Committees. We thank the reviewers of the original manuscript for many insightful suggestions and comments.
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All the authors are salaried (T.N.C.W.) or financially supported (R.H.v.H. and W.V.V.) by the Medicines for Malaria Venture, which has a stake in developing many of the drugs cited in this Review.
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FURTHER INFORMATION
Glossary
- Chemotypes
-
Families of molecules with similar chemical structures that share biological or therapeutic effects. Many distinct chemotypes may have the same biological activity.
- Chemoprotection
-
In the context of malaria, chemoprotection refers to medicines that prevent healthy individuals from contracting malaria. Such drugs are used by travellers but are also considered for mass eradication campaigns.
- Target candidate profiles
-
A specific set of quantitative criteria that a molecule must be predicted of achieving before it is considered for development. These criteria typically involve biological activity, pharmacokinetics and, in malaria, cost of goods. The target product profile is the definition of the specifications for the final medicine, which, for malaria, may consist of several active molecules.
- Herd immunity
-
Immune protection that occurs when an entire population, including those without immunity themselves, is protected from an infectious disease owing to the high rate of immunity within that population.
- Stringent regulatory authorities
-
Regulatory agencies from the European Union (for example, the European Medicines Agency), the USA (the Food and Drug Administration) and Japan (the Ministry of Health, Labour, and Welfare), all of which are members of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and other agencies that adhere to the same guidelines, such as in Switzerland, Australia and Canada.
- Prequalified
-
The WHO (World Health Organization) prequalification process is a formal assessment of diagnostics, medicines and vaccines, including review of the clinical dossier and the manufacturing and stability data, and site visits to manufacturers. This is a centralized procedure to approve products for purchase by specialized agencies of the United Nations.
- Blood stages
-
Early steps in the asexual, intra-erythrocytic replication cycle include the attachment of the Plasmodium spp. merozoites to blood cells, reorientation, irreversible attachment, junction formation, parasitophorous vacuole formation and invasion. The resulting immature trophozoite ring stage progresses into the mature tro-phozoite and schizont stages, which ruptures the blood cell to release new merozoites.
- Standard membrane feeding assays
-
Assays that measure the transmission of Plasmodium parasites back to mosquitoes; the insects' uptake of blood gametocytes and their successful mating is measured by counting (post-zygotic) midgut oocysts (the only route to re-infection). These assays involve mosquitoes feeding on human blood or serum through a membrane.
- Hypnozoites
-
Latent liver stages of Plasmodium vivax and Plasmodium ovale, species that are predominant in South and Southeast Asia and South America but only in Ethiopia and Sudan in Africa. Hypnozoites can remain dormant for weeks or even years, and carriers remain symptom-free until a relapse occurs.
- Human experimentally induced infection model
-
A model for malaria in which human volunteers are infected with Plasmodium parasites either by injection with infected erythrocytes (or sporozoites) or from the bite of an infected mosquito. Valuable pharmacokinetic and pharmacodynamic information of candidate drugs can thus be obtained at safe, well-monitored parasitaemia levels that are many orders of magnitude below those that induce symptoms.
- Heteroatoms
-
In organic chemistry, this term refers to all atoms that are not C or H. In the context of medicinal chemistry, novel heteroatoms refer to atoms not usually found in drugs (which are C, H, O, N, S and halogens).
- Gametocytes
-
Asexually replicating Plasmodium parasites in erythrocytes occasionally differentiate into gametocytes. These forms of the parasite are the only forms that can be taken up by mosquitoes, mate and propagate disease.
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Wells, T., van Huijsduijnen, R. & Van Voorhis, W. Malaria medicines: a glass half full?. Nat Rev Drug Discov 14, 424–442 (2015). https://doi.org/10.1038/nrd4573
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DOI: https://doi.org/10.1038/nrd4573
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