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Chemical interrogation of the malaria kinome.

Publication ,  Journal Article
Derbyshire, ER; Zuzarte-Luís, V; Magalhães, AD; Kato, N; Sanschagrin, PC; Wang, J; Zhou, W; Miduturu, CV; Mazitschek, R; Sliz, P; Mota, MM ...
Published in: Chembiochem : a European journal of chemical biology
September 2014

Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small-molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood-stage malaria. Most of the screening hits inhibited both liver- and blood-stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin-dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual-stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.

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Published In

Chembiochem : a European journal of chemical biology

DOI

EISSN

1439-7633

ISSN

1439-4227

Publication Date

September 2014

Volume

15

Issue

13

Start / End Page

1920 / 1930

Related Subject Headings

  • Small Molecule Libraries
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Plasmodium
  • Organic Chemistry
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Malaria
  • Liver
 

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Derbyshire, E. R., Zuzarte-Luís, V., Magalhães, A. D., Kato, N., Sanschagrin, P. C., Wang, J., … Clardy, J. (2014). Chemical interrogation of the malaria kinome. Chembiochem : A European Journal of Chemical Biology, 15(13), 1920–1930. https://doi.org/10.1002/cbic.201400025
Derbyshire, Emily R., Vanessa Zuzarte-Luís, Andreia D. Magalhães, Nobutaka Kato, Paul C. Sanschagrin, Jinhua Wang, Wenjun Zhou, et al. “Chemical interrogation of the malaria kinome.Chembiochem : A European Journal of Chemical Biology 15, no. 13 (September 2014): 1920–30. https://doi.org/10.1002/cbic.201400025.
Derbyshire ER, Zuzarte-Luís V, Magalhães AD, Kato N, Sanschagrin PC, Wang J, et al. Chemical interrogation of the malaria kinome. Chembiochem : a European journal of chemical biology. 2014 Sep;15(13):1920–30.
Derbyshire, Emily R., et al. “Chemical interrogation of the malaria kinome.Chembiochem : A European Journal of Chemical Biology, vol. 15, no. 13, Sept. 2014, pp. 1920–30. Epmc, doi:10.1002/cbic.201400025.
Derbyshire ER, Zuzarte-Luís V, Magalhães AD, Kato N, Sanschagrin PC, Wang J, Zhou W, Miduturu CV, Mazitschek R, Sliz P, Mota MM, Gray NS, Clardy J. Chemical interrogation of the malaria kinome. Chembiochem : a European journal of chemical biology. 2014 Sep;15(13):1920–1930.
Journal cover image

Published In

Chembiochem : a European journal of chemical biology

DOI

EISSN

1439-7633

ISSN

1439-4227

Publication Date

September 2014

Volume

15

Issue

13

Start / End Page

1920 / 1930

Related Subject Headings

  • Small Molecule Libraries
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Plasmodium
  • Organic Chemistry
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Malaria
  • Liver