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

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

  • Cell Chem Biol. 2025 Jun 19;32(6):826-838.e13. doi: 10.1016/j.chembiol.2025.05.001.
Irene Molina 1,  Ryan Mansell 2,  Rui Liang 3,  Benigno Crespo 1,  Margarita Puente 4,  Virginia Franco 1,  Sara Viera 1,  Isabel Camino 5,  Anas Saadeddin 5,  Peter Bellotti 6,  Annie Leung 7,  Sam Henning 2,  Shan Sun 3,  Mikayla Herring 2,  Celia Lopez 1,  Carmen Cuevas 1,  Peter Pogány 8,  Beatriz Urones 1,  Leigh Baxt 3,  Esther Fernández 1,  Jacob Geri 6,  Laura Kirkman 9,  Björn F C Kafsack 10,  Lydia Mata-Cantero 11
Affiliations

Affiliations

  • 1 Global Health Medicines R&D, GSK, Tres Cantos, CP28760 Madrid, Spain.
  • 2 Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 3 Sanders Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, USA.
  • 4 Discovery Chemistry, GSK, Tres Cantos, CP28760 Madrid, Spain.
  • 5 R&D Pre-clinical Sciences DMPK, Tres Cantos, CP28760 Madrid, Spain.
  • 6 Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
  • 7 Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY 10021, USA.
  • 8 Data and Predictive Sciences, Research Technologies, R&D, GSK Medicine Research Centre, Stevenage SG12NY, UK.
  • 9 Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY 10021, USA.
  • 10 Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: kafsacklab@gmail.com.
  • 11 Global Health Medicines R&D, GSK, Tres Cantos, CP28760 Madrid, Spain. Electronic address: lydia.c.mata@gsk.com.
PMID: 40412380 DOI: 10.1016/j.chembiol.2025.05.001
Abstract

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.

Keywords

CLAG3; HTS; P. falciparum; PSAC; antimalarial; inhibitors; malaria; nutrient-restricted-media; physiological-media; screening.

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