Targeting the Plasmodium falciparum IspE Enzyme

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC

ACS Applied Electronic Materials Pub Date : 2024-10-25 DOI:10.1021/acsomega.4c0603810.1021/acsomega.4c06038

Eleonora Diamanti, Annina M. Steinbach, Lais P. de Carvalho, Henni-Karoliina Ropponen, Antoine Lacour, Rawia Hamid, Sidra Eisa, Patricia Bravo, Spyridon Bousis, Boris Illarionov, Markus Fischer, Mostafa M. Hamed, Nina C. Bach, Matthias Rottmann, Jana Held, Matthias Witschel, Stephan A. Sieber and Anna K. H. Hirsch*,

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Abstract

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. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the PfIspE enzyme. Our approach toward a PfIspE inhibitor comprises in vitro 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 (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.

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以恶性疟原虫 IspE 酶为靶标

恶性疟原虫中的 IspE 酶被认为是一个极具吸引力的药物靶点，因为它对寄生虫的生存至关重要，而且在人类蛋白质组中并不存在。然而，至今仍没有小分子抑制剂能解决这个问题。在本研究中，我们针对 PfIspE 酶进行了高通量筛选。我们寻找 PfIspE 抑制剂的方法包括体外筛选、结构-活性关系研究、使用 AlphaFold 模型检查对接位置，最后通过探针结合和十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）分析进行目标验证。新合成的探针（23）含有一个二氮杂环和一个炔基，这使我们能够在人体细胞（HEK293 细胞）裂解液存在的情况下证明它与 IspE 的结合，并证明探针 23 和该系列的最佳抑制剂（19）都在竞争同一个 IspE 结合位点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Electronic Materials Multiple-

CiteScore

7.20

自引率

4.30%

发文量

567