Drug discovery

Chemical diversity targets malaria

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A molecule selected from a library of compounds that have structures similar to natural products targets several stages of the malarial parasite's life cycle, offering single-dose treatment of the disease in mouse models. See Article p.344

Eliminating malaria would save more than 400,000 lives annually, mainly those of young children in sub-Saharan Africa, and prevent the approximately 200 million cases of the disease that arise each year1. Achieving this will require medicines that can eliminate all three stages of Plasmodium parasite infection in humans. On page 344, Kato et al.2 report compounds, known as bicyclic azetidines, that display this multistage activity.

Kato and colleagues' work comes at a pivotal time. Malaria treatments rely on artemisinin-based combination therapies (ACTs), which combine an artemisinin-based compound with a second antimalarial drug. The rapid efficacy and global implementation of ACTs, coupled with increased mosquito-vector control efforts, have halved malaria death rates in the past 15 years1. However, artemisinin resistance has emerged and is now widespread in southeast Asia3. This places the partner drugs under increased evolutionary selection pressure for the development of resistance. In Cambodia, the ACT of dihydroartemisinin and piperaquine is failing rapidly because of resistance to both compounds4. Historical precedents suggest that resistance to first-line ACT agents might take hold in Africa next. There is thus an urgent need to develop more medicines.

The first stage of Plasmodium infection in humans is an asymptomatic infection of the liver; the second stage occurs when asexual parasites cause disease by infecting red blood cells; and at the third stage, parasites form sexual-stage gametocytes in red blood cells that, once mature, can be transmitted to Anopheles mosquitoes (Fig. 1). To identify potential multistage inhibitors, Kato et al. first carried out a high-throughput screen using in vitro cultures of asexual blood-stage parasites of Plasmodium falciparum, the most lethal of the human malarial parasites.

Figure 1: A compound that targets all parasite stages of malarial infection.
figure1

Malaria is caused by infection with Plasmodium parasites that progress through three main stages in the host. The first stage is an asymptomatic liver infection. Then parasites infect red blood cells at the disease-causing asexual blood stage. Parasites can also form gametocytes inside red blood cells, which can be taken up from the bloodstream by mosquitoes to transmit the disease onwards. Current artemisinin-based malarial treatments target asexual blood stages and immature gametocytes. By screening a chemical library for compounds active against different stages of the Plasmodium parasite's life cycle, Kato et al.2 identified the compound BRD7929, which, when tested against the human parasite Plasmodium falciparum or the rodent species Plasmodium berghei in mouse models, provided a single-dose cure and was able to prevent malaria and block onward transmission of the parasite. Me, methyl group.

The authors tested a library of approximately 100,000 compounds to search for parasite growth inhibitors. These compounds were produced using a technique known as diversity-oriented synthesis, in which chemical structures are built and coupled to generate molecules in a process inspired by the diversity and structural complexity of naturally occurring compounds5. Kato and colleagues then tested their inhibitory compounds against asexual blood-stage parasites from a panel of parasite strains resistant to known antimalarial agents, and extended the assays to liver and gametocyte-stage parasites.

The authors' screens identified several series of 'hits' that acted on known malarial-drug-target proteins, such as P. falciparum ATP4, PI4K and DHODH (ref. 6), as well as a wealth of other hits (including bicyclic azetidines) that have potentially new modes of action. The hits are documented at the Malaria Therapeutics Response Portal website (http://portals.broadinstitute.org/mtrp), which is a valuable resource for future antimalarial-drug discovery and development efforts.

By selecting for drug resistance in cultured parasites and applying whole-genome DNA-sequence analysis to identify genetic changes, Kato et al. obtained evidence that the bicyclic azetidines target an enzyme termed cytosolic P. falciparum phenylalanyl-tRNA synthetase (Pf PheRS). This finding was confirmed in biochemical assays demonstrating chemical inhibition of the enzyme. PheRS acts on transfer-RNA molecules, enabling them to deliver the amino acid phenylalanine to nascent proteins during the vital cellular process of messenger-RNA translation and protein synthesis. tRNA synthetase enzymes have emerged in recent years as a promising class of antimalarial target7.

Kato et al. tested their lead bicyclic azetidine compound BRD7929 in mouse models of malarial infection using either P. falciparum or the rodent parasite, Plasmodium berghei. The authors found that a single, low dose of BRD7929 was sufficient to eliminate infections at the liver or asexual blood stages, affording complete cure. Transmission-blocking activity at the gametocyte stage was also observed at drug concentrations that achieved single-dose cures of asexual blood-stage infections. If similar efficacy could be achieved in treating human infections, it would change the landscape of disease treatment and control by providing a powerful tool for malaria elimination6.

The inspired decision by Kato and colleagues to screen natural-product-like compounds amenable to synthesis was one key to the study's success. The other notable factor was the remarkable coordination between the various collaborating research laboratories. This enabled testing of Pf PheRS inhibitors throughout the parasitic life cycle, as well as chemical optimization and pharmacological evaluation of the compounds that was achieved by assessing the relationship between their structures and activities. Of course, there is no guarantee that bicyclic azetidines will ultimately yield a licensed medicine with the desired single-dose cure, prevention and transmission-blocking properties.

BRD7929 displayed good oral bioavailability (the amount of drug that reaches the bloodstream after oral ingestion) and other promising pharmacological properties, including a long half-life — approximately 32 hours in mice. Yet it remains possible that this compound might encounter setbacks during further testing, such as toxicological issues or problems in drug selectivity for the parasite enzyme over its human counterpart. The establishment by Kato et al. of a functional screen that uses Pf PheRS provides opportunities to identify alternative chemical scaffolds to bicyclic azetidines, if necessary.

Given the constant concern of antimalarial drug resistance8, Kato and colleagues tested their compound for resistance development. They found that bicyclic azetidine treatment selects for resistance with a frequency of greater than 1 per 109 parasites, which compares favourably with other preclinical drug candidates9,10. To place this in context, an infected, symptomatic individual can harbour up to 1012 parasites6. Therefore, resistance might emerge in settings in which the disease is endemic, although its ability to become established and spread is tempered by many factors, including host immunity and parasite fitness. Resistance concerns can be mitigated by combining PheRS inhibitors with pharmacologically matched inhibitors that have a different mode of action.

Future studies will also be needed to evaluate whether PheRS inhibitors can effectively eliminate another human malaria parasite, Plasmodium vivax, which has a dormant stage of liver infection. These dormant parasites can reinitiate growth and cause relapse months or even years after the primary infection. The need for a drug to target dormant P. vivax liver infections is particularly acute because primaquine, the only licensed drug treatment for this form of the disease, can be highly toxic to people with certain types of deficiency for the enzyme glucose-6-phosphate dehydrogenase — a common genetic trait6.

Single-dose malaria cures, combined with safe and effective prevention and transmission-blocking measures, would be a tremendous boon to afflicted populations, whose socio-economic challenges are exacerbated by this debilitating disease. The world would be a healthier community of nations if this goal were to be achieved. The current study demonstrates the power of coordinating the multifaceted research activities required to achieve such a goal.Footnote 1

Notes

  1. 1.

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References

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    WHO. World Malaria Report 2015 www.who.int/malaria/publications/world-malaria-report-2015/report/en (2015).

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    Kato, N. et al. Nature 538, 344–349 (2016).

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    Wells, T. N. C., Hooft van Huijsduijnen, R. & Van Voorhis, W. C. Nature Rev. Drug Discov. 14, 424–442 (2015).

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    Corey, V. C. et al. Nature Commun. 7, 11901 (2016).

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    Baragaña, B. et al. Nature 522, 315–320 (2015).

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    Phillips, M. A. et al. Sci. Transl. Med. 7, 296ra111 (2015).

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Correspondence to David A. Fidock.

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Fidock, D. Chemical diversity targets malaria. Nature 538, 323–325 (2016) doi:10.1038/nature19481

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