PSAC通道在疟疾寄生虫存活中的关键作用是通过相关营养水平下的表型筛选来实现的

IF 7.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2025-06-19 DOI:10.1016/j.chembiol.2025.05.001

Irene Molina , Ryan Mansell , Rui Liang , Benigno Crespo , Margarita Puente , Virginia Franco , Sara Viera , Isabel Camino , Anas Saadeddin , Peter Bellotti , Annie Leung , Sam Henning , Shan Sun , Mikayla Herring , Celia Lopez , Carmen Cuevas , Peter Pogány , Beatriz Urones , Leigh Baxt , Esther Fernández , Lydia Mata-Cantero

{"title":"PSAC通道在疟疾寄生虫存活中的关键作用是通过相关营养水平下的表型筛选来实现的","authors":"Irene Molina , Ryan Mansell , Rui Liang , Benigno Crespo , Margarita Puente , Virginia Franco , Sara Viera , Isabel Camino , Anas Saadeddin , Peter Bellotti , Annie Leung , Sam Henning , Shan Sun , Mikayla Herring , Celia Lopez , Carmen Cuevas , Peter Pogány , Beatriz Urones , Leigh Baxt , Esther Fernández , Lydia Mata-Cantero","doi":"10.1016/j.chembiol.2025.05.001","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>in vivo</em> humanized mouse model was confirmed.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 826-838.e13"},"PeriodicalIF":7.2000,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels\",\"authors\":\"Irene Molina , Ryan Mansell , Rui Liang , Benigno Crespo , Margarita Puente , Virginia Franco , Sara Viera , Isabel Camino , Anas Saadeddin , Peter Bellotti , Annie Leung , Sam Henning , Shan Sun , Mikayla Herring , Celia Lopez , Carmen Cuevas , Peter Pogány , Beatriz Urones , Leigh Baxt , Esther Fernández , Lydia Mata-Cantero\",\"doi\":\"10.1016/j.chembiol.2025.05.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>in vivo</em> humanized mouse model was confirmed.</div></div>\",\"PeriodicalId\":265,\"journal\":{\"name\":\"Cell Chemical Biology\",\"volume\":\"32 6\",\"pages\":\"Pages 826-838.e13\"},\"PeriodicalIF\":7.2000,\"publicationDate\":\"2025-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Chemical Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2451945625001369\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2451945625001369","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

对一线治疗药物的耐药性不断蔓延，需要寻找新型抗疟药物。标准筛选条件的局限性促使我们开发了一种使用培养基的检测方法，该培养基更接近地反映了人血清中的营养水平，以揭示新的治疗相关的寄生虫途径。我们的方法通过测试22k个化合物和完整的750k个化合物筛选得到验证，并确定了29个在营养受限培养基中具有较高活性的化学型，并进一步进行了表征。通过化学基因组学和创新的光催化接近标记蛋白质组学的结合，我们确定了两个化合物的目标是plasmodial表面阴离子通道（PSAC）的CLAG3组分。引人注目的是，所选择的其他29种化学型中的每一种也被发现阻断PSAC活性，突出了这种营养通道对寄生虫在生理条件下生存的重要性。PSAC抑制剂在人体内小鼠模型中的作用得到了证实。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels

查看原文本刊更多论文

The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels

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.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.