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Antimalarial drugs

A treasure trove of potential antimalarials

Nature Reviews Drug Discovery volume 9, pages 516–517 (2010)Cite this article

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The battle to control malaria infection has been hampered by many factors, including emerging drug resistance. Now, two papers published in Nature have opened up the door to a wealth of compounds that can be explored in the development of novel antimalarials, in particular against Plasmodium falciparum, the parasite species that causes the most deaths.

In the second paper, which was a collaborative effort between academic institutions and GlaxoSmithKline, a chemical genetic screen was used to identify novel antimalarials. An initial screen of 309,474 compounds yielded 1,300 hits, which then underwent additional rounds of selection and cross-validation to produce 172 structurally distinct compounds for further analysis. All of the hits had ≤2 μM maximum effective concentration against P. falciparum strains that were either sensitive or resistant to chloroquine (a widely used antimalarial). Interestingly, most compounds had additive or minor synergies with existing antimalarials and minimal cross-resistance with current drugs. In a screen against 61 potential malaria targets, 19 new inhibitors of 4 validated drug targets and 15 novel targets were identified. Moreover, of the compounds tested, good pharmacokinetic and pharmacodynamic properties were observed, with 78% of molecules having no violations of the Lipinski rule of five (a predictor of oral bioavailability). One compound that had the most potential in terms of inhibitory activity and its pharmacokinetic profile was tested in a mouse model of malaria. Parasitaemia was suppressed by up to 90% when the compound was given in doses of 100 mg per kg, twice a day for 3 days.

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References

ORIGINAL RESEARCH PAPERS

  1. Gamo, F.-J. et al. Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305–310 (2010)

    Article  CAS  Google Scholar 

  2. Guiguemde, W. A. et al. Chemical genetics of Plasmodium falciparum. Nature 465, 311–315 (2010)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Wells, T. N. C., Alonso, P. L. & Gutteridge, W. E. New medicines to improve control and contribute to the eradication of malaria. Nature Rev. Drug Discov. 8, 879–891 (2009)

    Article  CAS  Google Scholar 

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Authors
  1. Man Tsuey Tse
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Tse, M. A treasure trove of potential antimalarials. Nat Rev Drug Discov 9, 516–517 (2010). https://doi.org/10.1038/nrd3209

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  • DOI: https://doi.org/10.1038/nrd3209

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