Drug discovery

Priming the antimalarial pipeline

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Emerging resistance to existing antimalarial drugs could nullify efforts to eliminate this deadly disease. The discovery of thousands of agents active against malaria parasites offers hope for developing new drugs.

Malaria affects hundreds of millions of people worldwide, and claims hundreds of thousands of lives every year. These grim statistics could rise even higher should resistance to the existing antimalarial drugs develop further. It is against this backdrop that the papers of Gamo et al.1 and Guiguemde et al.2 merit celebration — in this issue, they describe the identification and chemical structures of vast numbers of compounds, each with the potential to be developed into tomorrow's antimalarial drugs.

For much of the twentieth century, malaria was treated with the fast-acting and inexpensive drugs chloroquine and pyrimethamine–sulphadoxine. From the 1960s onwards, these drugs progressively succumbed to the appearance and spread of resistance around the world. By the early 1990s, malaria's percentage contribution to 'all-cause mortality' in African infants was climbing3, in some areas accounting for nearly 50% of deaths. These facts are attributable almost exclusively to Plasmodium falciparum, one of the five Plasmodium species that cause malaria in humans.

Currently, the only fully effective class of antimalarial drug is the artemisinins. These are remarkably potent against the asexual blood stage of the parasite's life cycle, during which it replicates inside human red blood cells and causes disease. Artemisinin-based combination therapies (ACTs) have now been adopted globally as the first line of treatment. Together with mosquito-control measures such as insecticide-treated bednets, ACTs have driven down malaria rates across sub-Saharan Africa, where the disease exerts the greatest burden4.

But despite intensifying elimination campaigns5, the prospect of resistance remains. Delayed rates of parasite clearance after administration of ACTs are already evident near the Thai–Cambodian border6 — a hotbed of multidrug resistance. Malaria control is therefore at a pivotal stage. Continued efficacy of ACTs and their sustained use, along with mosquito-vector control programmes, could well produce a remarkable global-health triumph. Alternatively, resistance could wipe out artemisinins, and malaria could resurge to former levels of virulence, causing millions of deaths per year. One hopes that the compounds described by Gamo et al.1 (page 305) and Guiguemde et al.2 (page 311) will soon produce drugs that will tip this precarious situation in our favour.

Guiguemde et al. report an extraordinary multidisciplinary effort. They began by screening for compounds that inhibit the growth of asexual blood-stage P. falciparum in cultured red blood cells. The team used a chemically diverse library of almost 310,000 compounds, selected to maximize diversity while retaining clusters of related agents to explore structure–activity relationships. More than 1,100 compounds met the authors' criterion of inhibiting parasite growth by 80% when tested at a concentration of 7 micromolar. Promisingly, most of the 172 compounds the researchers then scrutinized more closely had novel chemical structures, and at least 80% of these seemed to act on parasite targets distinct from those affected by the current drugs.

Strains of P. falciparum that are resistant to the existing antimalarial drugs showed minimal cross-resistance to the shortlisted compounds2. Furthermore, two classes of the chemicals worked in synergy with ACTs — a favourable attribute given the current focus on drug combinations to reduce the risk of resistance emerging rapidly.

Guiguemde and colleagues also investigated their compounds' effect on other pathogenic parasites (Toxoplasma, Leishmania and trypanosomes) and on replicating human cell lines, and found that most of the compounds were highly selective for Plasmodium. Preliminary pharmacokinetic analyses — investigations related to how a compound is absorbed, distributed, metabolized and eliminated by the body — suggested that many compounds were generally suitable for further development. As a proof of principle, the authors showed one compound to be efficacious in treating malaria in a mouse model, albeit at concentrations 25-fold higher than the effective dose of chloroquine in the same animal model.

Gamo et al.1 used GlaxoSmithKline's in-house chemical library to screen almost 2 million compounds against asexual blood-stage P. falciparum. Setting a similar threshold of greater than 80% growth inhibition, in this case at a cut-off of 2 micromolar, the authors identified more than 13,500 active compounds. Of these, 8,000 were equally active against multidrug-resistant P. falciparum parasites, and fewer than 2,000 displayed some non-selective activity against a human liver-cancer cell line. Gamo and colleagues confirmed the relevance of their compounds by identifying among them several representatives of all existing antimalarial drug classes (Table 1), with the exception of the artemisinins, which were known to be absent from the starting library. Significantly, more than 11,000 of the new hits were previously proprietary to GlaxoSmithKline and are now made accessible to the general research community for the first time.

Table 1 Existing antimalarial drugs and their use

On the basis of their in-house annotations of candidate human or microbial targets for more than 4,200 compounds, Gamo et al. predict that many active compounds might target kinase enzymes of P. falciparum. If confirmed, this would constitute an important new direction for antimalarial drug development — one that might cross paths with researchers exploiting the vast chemical repositories developed to target kinases in other disorders, including solid-tumour cancers, inflammation, arthritis, diabetes and cardiovascular disease.

Gamo and colleagues1 do not go as far as Guiguemde et al.2 in experimentally determining potential parasite targets or reporting preliminary pharmacokinetic or pharmacodynamic data — this would be a huge task for so many compounds. As such, their study provides only starting points to test future hypotheses concerning drug action. Nonetheless, it is momentous that a large pharmaceutical company has made its antimalarial drug-discovery data, including chemical structures, freely available. These data are fully searchable through the European Bioinformatics Institute's ChEMBL database7.

Neither group1,2 claims to have discovered the next antimalarial drug. Instead, they provide a remarkable diversity of novel chemical structures on which to base new antimalarial drug-discovery and development campaigns. Comparison of these biologically active compounds — and an earlier, partially described set8 identified in a high-throughput screen against P. falciparum — should be a first step. Compounds that prove to be potent in rodent models, cheap to synthesize, safe and unaffected by existing mechanisms of resistance should also be evaluated for activity against other stages of the Plasmodium life cycle. These include the sexual blood stage responsible for transmission to the mosquito vectors, and the asymptomatic liver stage that precedes blood-stage infection. Finally, activity must also be assessed against Plasmodium vivax — a species that, outside Africa, causes more cases of malaria than P. falciparum and can, according to a clinical study in Indonesia9, cause severe, and at times fatal, disease.

Innovative efforts by many organizations — notably the Medicines for Malaria Venture in Geneva, Switzerland — have in recent years greatly accelerated the development and licensing of new antimalarial drugs10. But the discovery pipeline remains woefully thin, and there are precious few alternatives to artemisinins. These reports1,2 offer tremendous opportunities to develop the next generation of antimalarial drugs. They also sound a call for the academic and pharmaceutical sectors to rise to the challenge. This should include a concerted chemical-genomics effort to identify the most appropriate targets in the parasite. Time is of the essence.


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