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Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.

Publication ,  Journal Article
Reker, D; Seet, M; Pillong, M; Koch, CP; Schneider, P; Witschel, MC; Rottmann, M; Freymond, C; Brun, R; Schweizer, B; Illarionov, B; Bacher, A ...
Published in: Angewandte Chemie (International ed. in English)
July 2014

The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.

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Published In

Angewandte Chemie (International ed. in English)

DOI

EISSN

1521-3773

ISSN

1433-7851

Publication Date

July 2014

Volume

53

Issue

27

Start / End Page

7079 / 7084

Related Subject Headings

  • Pyrroles
  • Pyridazines
  • Protozoan Proteins
  • Protein Kinases
  • Plasmodium falciparum
  • Plasmodium berghei
  • Organic Chemistry
  • Humans
  • Hep G2 Cells
  • Erythrocytes
 

Citation

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Reker, D., Seet, M., Pillong, M., Koch, C. P., Schneider, P., Witschel, M. C., … Schneider, G. (2014). Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents. Angewandte Chemie (International Ed. in English), 53(27), 7079–7084. https://doi.org/10.1002/anie.201311162
Reker, Daniel, Michael Seet, Max Pillong, Christian P. Koch, Petra Schneider, Matthias C. Witschel, Matthias Rottmann, et al. “Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.Angewandte Chemie (International Ed. in English) 53, no. 27 (July 2014): 7079–84. https://doi.org/10.1002/anie.201311162.
Reker D, Seet M, Pillong M, Koch CP, Schneider P, Witschel MC, et al. Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents. Angewandte Chemie (International ed in English). 2014 Jul;53(27):7079–84.
Reker, Daniel, et al. “Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.Angewandte Chemie (International Ed. in English), vol. 53, no. 27, July 2014, pp. 7079–84. Epmc, doi:10.1002/anie.201311162.
Reker D, Seet M, Pillong M, Koch CP, Schneider P, Witschel MC, Rottmann M, Freymond C, Brun R, Schweizer B, Illarionov B, Bacher A, Fischer M, Diederich F, Schneider G. Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents. Angewandte Chemie (International ed in English). 2014 Jul;53(27):7079–7084.
Journal cover image

Published In

Angewandte Chemie (International ed. in English)

DOI

EISSN

1521-3773

ISSN

1433-7851

Publication Date

July 2014

Volume

53

Issue

27

Start / End Page

7079 / 7084

Related Subject Headings

  • Pyrroles
  • Pyridazines
  • Protozoan Proteins
  • Protein Kinases
  • Plasmodium falciparum
  • Plasmodium berghei
  • Organic Chemistry
  • Humans
  • Hep G2 Cells
  • Erythrocytes