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New medicines to improve control and contribute to the eradication of malaria

Nature Reviews Drug Discovery volume 8, pages 879–891 (2009)Cite this article

Key Points

  • Currently available medicines against Plasmodium falciparum are largely fixed-dose artemisinin-based combination therapies; the combination serves to protect individual medicines against resistance. For Plasmodium vivax radical cure, the standard of care is still primaquine, with no major breakthroughs in the past 60 years.

  • New medicines that block transmission and dormant reservoirs of malaria parasite, such as the hypnozoite of P. vivax, will have an important role in the eradication of malaria.

  • Next-generation therapies after artemisinin include new synthetic endoperoxides. With the emergence of artemisinin resistance, it is important to confirm that these medicines will have activity against artemisinin-resistant strains.

  • New targets can come from an increase in our understanding of the parasite genome. More recently, screens against the whole parasite have also been successful. Screens against some pathways, such as purine and pyramidine metabolism, and mitochondrial electron transport, have produced interesting chemical series.

  • Laying out what a new medicine has to achieve to be successful (that is, determining the target product profile) is an important and often underestimated step in drug discovery and development. A key factor in antimalarial medicines is to ensure safety, especially as they are administered in countries where adverse-event reporting is often limited.

  • Over the past 10 years, there has been a change in the way medicines for malaria are discovered and developed. Increased interest from the pharmaceutical industry and charitable foundations has supported the work of the public–private partnerships in bringing forward a portfolio of new medicines, which will support the eradication agenda.

Abstract

Despite being one of the most prevalent tropical diseases, for many years malaria was not a commercial priority for the pharmaceutical industry. However, in response to the emergence and spread of resistance to the available antimalarial drugs, there has been a renaissance in the discovery and development of new medicines to control the disease in the last few years. The persistent threat of resistance means that new molecules with novel mechanisms of action are continually required. Furthermore, the recent call for the elimination and eradication of malaria has prompted an extension of the stages of the life cycle of malaria parasites that should be targeted by new molecules. Recent advances in genome-based technologies and in in vitro screening of whole parasites have broadened the range of therapeutic targets and are accelerating the development of a new generation of treatments for both malaria control and eradication.

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Figure 1: Life cycle of the malaria parasite.
Figure 2: Structures of selected key antimalarial compounds.
Figure 3: The global antimalarial drug portfolio (June 2009).

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Acknowledgements

We thank our colleagues on the staff and External Scientific Advisory Committee for MMV and our research and development partners, and the various governments, foundations and charities that have provided the finance required to operate this PPP. We apologize to those whose work was not cited due to space constraints.

Author information

Authors and Affiliations

  1. Medicines for Malaria Venture, 20 Route de Pré-Bois, Geneva, 1215, Switzerland

    Timothy N. C. Wells & Winston E. Gutteridge

  2. Barcelona Centre for International Health Research, Hospital Clinic/IDIBAPS, Universitat de Barcelona, Barcelona, Spain

    Pedro L. Alonso

  3. Centro de Investigação em Saúde de Manhiça, Manhiça, Maputo, Mozambique

    Pedro L. Alonso

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  1. Timothy N. C. Wells
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  3. Winston E. Gutteridge
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Correspondence to Timothy N. C. Wells.

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FURTHER INFORMATION

Medicines for Malaria Venture

Affordable Medicines Facility for Malaria

Global Fund to Fight AIDS, Tuberculosis and Malaria

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

Malaria Eradication Research Agenda

Roll Back Malaria

Glossary

Artemisinin-based combination therapy

(ACT). A treatment regimen for malaria, usually comprising two medicines, one of which is artemisinin or one of its derivatives. ACTs come in two varieties: co-packaged or the preferred co-formulated.

Merozoite

The life cycle stage in which the malaria parasite has the ability to penetrate and infect red blood cells. The parasite expresses receptors and proteolytic enzymes on its surface to facilitate this process.

Hypnozoite

The dormant liver stage of P. vivax and P. ovale. The parasite remains in hepatocytes after the other liver-stage parasites have replicated and released their merozoites. Hypnozoites are the source of malaria relapses.

Gametocyte

The male and female sexual stages of the malaria parasite. Formed in the red blood cells, it remains dormant unless taken up by a mosquito, in which it forms gametes, which fuse to form the ookinete.

Fever clearance time

The time taken for body temperature to return to normal levels after the first dose of an antimalarial has been given.

Parasite clearance time

The time taken for asexual parasites to no longer be detectable microscopically after the first dose of an antimalarial has been given.

Causal prophylactic activity

Effect of antimalarial drugs that prevent sporozoite infection or replication of parasites in the liver, in contrast to suppressive prophylaxis in which replication of parasites in the blood is prevented.

ICH

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, which issues guidelines for good laboratory and clinical practice.

Reticulocyte

An immature red blood cell.

Apicoplast

An organelle that is present in malaria parasites and is thought to be a relic of the chloroplast. It contains DNA which codes for ∼30 plant-like proteins and bacteria-like ribosomes. A further 500 nuclear-encoded proteins of unknown phylogenetic origin are predicted to be targeted to this organelle.

Radical cure

The elimination from patients infected with P. vivax or P. ovale of all parasites, including the dormant liver hypnozoites. Unless this is done, patients will subsequently relapse.

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Wells, T., Alonso, P. & Gutteridge, W. New medicines to improve control and contribute to the eradication of malaria. Nat Rev Drug Discov 8, 879–891 (2009). https://doi.org/10.1038/nrd2972

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