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
Global Health Medicines R&D, GSK, Tres Cantos, CP28760 Madrid, Spain.
Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY 10065, USA.
Cell Chem Biol. 2025 Jun 19;32(6):826-838.e13. doi: 10.1016/j.chembiol.2025.05.001. Epub 2025 May 23.
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.
对一线治疗产生的耐药性传播促使人们寻找新型抗疟药物。标准筛选条件的局限性促使我们开发一种检测方法，该方法使用更能反映人血清中营养水平的培养基，以揭示新的具有治疗相关性的寄生虫途径。我们的方法通过测试22000种化合物进行验证，随后进行了完整的750000种化合物筛选，并鉴定出29种在营养受限培养基中具有更高活性的化学型，对其进行了进一步表征。通过化学基因组学和创新的光催化邻近标记蛋白质组学相结合，我们确定了两种化合物的靶点为疟原虫表面阴离子通道（PSAC）的CLAG3成分。引人注目的是，所选的其他29种化学型中的每一种也都被发现可阻断PSAC活性，突出了这种营养通道在生理条件下对寄生虫生存的重要性。PSAC抑制剂在体内人源化小鼠模型中的作用得到了证实。
