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A clinical drug library screen identifies astemizole as an antimalarial agent

Nature Chemical Biology volume 2, pages 415–416 (2006)Cite this article

Abstract

The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.

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Figure 1: Identification of astemizole as an antimalarial agent by screening a library of existing drugs.

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Acknowledgements

The authors thank T. Shapiro and S. Prigge for manuscript comments and P. Okinedo for advice and encouragement. This work was supported by The Johns Hopkins Malaria Research Institute, Fund for Medical Discovery and Department of Pharmacology and The Keck Foundation. D.J.S. is supported by National Institutes of Health RO1 A145774 and a Pew Scholars Award in Biomedical Sciences. C.R.C. is supported by the Congressionally Directed Breast Cancer Research Program Predoctoral Fellowship and by the National Institutes of Health Medical Scientist Training Program. The culturing of P. falciparum was supported by National Center for Research Resources grant GPDGCRC RR0052.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences. The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Curtis R Chong, Xiaochun Chen & Jun O Liu

  2. The Johns Hopkins Clinical Compound Screening Initiative, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Curtis R Chong, Jun O Liu & David J Sullivan Jr

  3. Medical Scientist Training Program, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Curtis R Chong

  4. W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Malaria Research Institute, The Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Lirong Shi & David J Sullivan Jr

  5. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jun O Liu

Authors
  1. Curtis R Chong
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  2. Xiaochun Chen
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  3. Lirong Shi
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  4. Jun O Liu
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  5. David J Sullivan Jr
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Contributions

C.C., J.L. and D.S. contributed to library design, construction and screening as well as manuscript preparation. X.C. assisted with the mouse malaria model. L.S. performed the P. falciparum in vitro screen.

Corresponding author

Correspondence to David J Sullivan Jr.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Comparison of The Johns Hopkins Clinical Compound Library with other libraries of existing drugs. (PDF 502 kb)

Supplementary Fig. 2

Selected screening results from drug classes of interest. (PDF 44 kb)

Supplementary Fig. 3

Astemizole reversibly inhibits heme crystallization and accumulates in the P. falciparum food vacuole. (PDF 156 kb)

Supplementary Table 1

Existing drugs that showed >50% inhibition of 3D7 proliferation at 10 μM. (PDF 34 kb)

Supplementary Methods (PDF 111 kb)

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Chong, C., Chen, X., Shi, L. et al. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2, 415–416 (2006). https://doi.org/10.1038/nchembio806

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