Targeting the <i>Plasmodium falciparum</i> IspE Enzyme
The enzyme IspE in <i>Plasmodium falciparum</i> is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the <i>Pf</i>IspE enzyme. Our approach toward a <i>Pf</i>IspE inhibitor comprises <i>in vitro</i> screening, structure-activity relationship studies, examining the docking position using an AlphaFold model, and finally target verification through probe binding and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The newly synthesized probe containing a diazirine and an alkyne moiety (<b>23</b>) allowed us to demonstrate its binding to IspE in the presence of a lysate of human cells (HEK293 cells) and to get evidence that both probe <b>23</b> and the best inhibitor of the series (<b>19</b>) compete for the same IspE binding site.
Authors
- Jana Held (ORCID: https://orcid.org/0000-0002-7970-1429)
- Markus Fischer (ORCID: https://orcid.org/0000-0001-7243-4199)
- Mostafa M. Hamed (ORCID: https://orcid.org/0000-0002-7374-6992)
- Rawia Hamid (ORCID: https://orcid.org/0000-0001-9211-6286)
- Annina M. Steinbach (ORCID: https://orcid.org/0000-0003-0707-3125)
- Nina C. Bach (ORCID: https://orcid.org/0009-0001-8834-7695)
- Henni‐Karoliina Ropponen (ORCID: https://orcid.org/0000-0002-1223-1063)
- Matthias Rottmann (ORCID: https://orcid.org/0000-0002-2207-7899)
- Eleonora Diamanti (ORCID: https://orcid.org/0000-0001-8392-5575)
- S. S. Eisa
- Stephan A. Sieber (ORCID: https://orcid.org/0000-0002-9400-906X)
- Spyridon Bousis
- Matthias Witschel (ORCID: https://orcid.org/0000-0003-0537-5146)
- Patricia Bravo (ORCID: https://orcid.org/0000-0001-5454-3826)
- Boris Illarionov (ORCID: https://orcid.org/0009-0007-8489-0651)
- Antoine Lacour
- Laís Pessanha de Carvalho (ORCID: https://orcid.org/0000-0002-3857-5462)
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
Institutions
- Swiss Tropical and Public Health Institute (CH)
- University of Basel (CH)
- Fischer (Germany) (DE)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Robert Bosch (Germany) (DE)
- Saarland University (DE)
Publication Details
- Journal
- ACS Omega
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1021/acsomega.4c06038
- Citations
- 1
- Primary Topic
- Plant biochemistry and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Universität Basel
- Deutsches Zentrum für Infektionsforschung
- Universität des Saarlandes
- Technische Universität München