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.
Authors
- Paolo Bellotti (ORCID: https://orcid.org/0000-0003-4839-8807)
- Benigno Crespo
- Björn F.C. Kafsack (ORCID: https://orcid.org/0000-0003-0089-1096)
- R. A. Mansell
- Virginia Franco
- Rui Liang (ORCID: https://orcid.org/0000-0003-2267-4885)
- Susan Henning
- Lydia Mata-Cantero (ORCID: https://orcid.org/0000-0002-1924-3614)
- Irene T. Molina‐Martínez (ORCID: https://orcid.org/0000-0002-9157-571X)
- Péter Pogány (ORCID: https://orcid.org/0000-0003-3536-0746)
- Sara Viera (ORCID: https://orcid.org/0000-0002-2025-4804)
- Isabel Camino (ORCID: https://orcid.org/0009-0005-4024-6894)
- Esther Fernández (ORCID: https://orcid.org/0000-0002-0507-8507)
- Leigh A. Baxt (ORCID: https://orcid.org/0000-0001-8286-3907)
- Mikayla Herring
- Shan Sun (ORCID: https://orcid.org/0000-0003-0349-2664)
- Jacob B. Geri (ORCID: https://orcid.org/0000-0002-9215-5610)
- Laura A. Kirkman (ORCID: https://orcid.org/0000-0003-4085-5540)
- Beatriz Urones
- Annie Leung
- Celia López
- Carmen Cuevas (ORCID: https://orcid.org/0000-0002-9116-2405)
- Anas Saadeddin
- Margarita Puente
Institutions
- Cornell University (US)
- Age UK (GB)
- GlaxoSmithKline (France) (FR)
- GlaxoSmithKline (Spain) (ES)
- Tri-Institutional Therapeutics Discovery Institute (US)
- Weill Cornell Medicine (US)
- GMV Innovating Solutions (Spain) (ES)
Publication Details
- Journal
- Cell chemical biology
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1016/j.chembiol.2025.05.001
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- National Institute of Allergy and Infectious Diseases