The enzyme IspE in Plasmodium falciparum is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome, and yet it has still not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the Pf IspE enzyme. Our approach toward a Pf IspE inhibitor comprises in vitro screening, structure−activity relationship studies, examining the docking position using an α-Fold 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 (23) 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 23 and the best inhibitor of the series (19) compete for the same IspE binding site.

Diamanti, E., Steinbach, A. M., de Carvalho, L. P., Ropponen, H.-K., Lacour, A., Hamid, R., Eisa, S., Bravo, P., Bousis, S., Illarionov, B., Fischer, M., Hamed, M. M., Bach, N. C., Rottmann, M., Held, J., Witschel, M., Sieber, S. A., Hirsch, A. K. H. "Targeting the Plasmodium falciparum IspE Enzyme" ACS Omega

Link: https://doi.org/10.1021/acsomega.4c06038

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