Cell chemical biology · 2025
The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Molina Irene, Mansell Ryan, Liang Rui, Crespo Benigno, Puente Margarita, Franco Virginia, Viera Sara, Camino Isabel, Saadeddin Anas, Bellotti Peter, Leung Annie, Henning Sam, Sun Shan, Herring Mikayla, Lopez Celia, Cuevas Carmen, Pogány Peter, Urones Beatriz, Baxt Leigh, Fernández Esther, Geri Jacob, Kirkman Laura, Kafsack Björn F C, Mata-Cantero Lydia
Аннотация
Spreading resistance to front-line treatments necessitate the search for new classes of antimalarials. Limitations of standard screening conditions lead us to develop an assay using culture media that more closely reflects nutrient levels in human serum to reveal new therapeutically relevant parasite pathways. Our approach was validated by testing 22k compounds followed by a full 750k compound screen and identified 29 chemotypes with higher activity in nutrient restricted media that were further characterized. Through a combination of chemo-genomics and innovative photocatalytic proximity labeling proteomics, we identified the target of two compounds as the CLAG3 component of the plasmodial surface anion channel (PSAC). Strikingly, every one of the other 29 chemotypes selected was also found to block PSAC activity, highlighting the importance of this nutrient channel for parasite survival under physiological conditions. The effect of PSAC inhibitors in the in vivo humanized mouse model was confirmed.