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Liver-stage malaria parasites vulnerable to diverse chemical scaffolds.

Publication ,  Journal Article
Derbyshire, ER; Prudêncio, M; Mota, MM; Clardy, J
Published in: Proceedings of the National Academy of Sciences of the United States of America
May 2012

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite's life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

May 2012

Volume

109

Issue

22

Start / End Page

8511 / 8516

Related Subject Headings

  • Treatment Outcome
  • Plasmodium falciparum
  • Plasmodium berghei
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Malaria, Falciparum
  • Malaria
  • Liver
  • Life Cycle Stages
 

Citation

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Derbyshire, E. R., Prudêncio, M., Mota, M. M., & Clardy, J. (2012). Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proceedings of the National Academy of Sciences of the United States of America, 109(22), 8511–8516. https://doi.org/10.1073/pnas.1118370109
Derbyshire, Emily R., Miguel Prudêncio, Maria M. Mota, and Jon Clardy. “Liver-stage malaria parasites vulnerable to diverse chemical scaffolds.Proceedings of the National Academy of Sciences of the United States of America 109, no. 22 (May 2012): 8511–16. https://doi.org/10.1073/pnas.1118370109.
Derbyshire ER, Prudêncio M, Mota MM, Clardy J. Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proceedings of the National Academy of Sciences of the United States of America. 2012 May;109(22):8511–6.
Derbyshire, Emily R., et al. “Liver-stage malaria parasites vulnerable to diverse chemical scaffolds.Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 22, May 2012, pp. 8511–16. Epmc, doi:10.1073/pnas.1118370109.
Derbyshire ER, Prudêncio M, Mota MM, Clardy J. Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proceedings of the National Academy of Sciences of the United States of America. 2012 May;109(22):8511–8516.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

May 2012

Volume

109

Issue

22

Start / End Page

8511 / 8516

Related Subject Headings

  • Treatment Outcome
  • Plasmodium falciparum
  • Plasmodium berghei
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Malaria, Falciparum
  • Malaria
  • Liver
  • Life Cycle Stages