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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Screening of a chemogenetic library unveils dual-stage antiplasmodials with low cytotoxicity

  • Laura Torres1
  • Matthew E. Fishbaugher2
  • Melanie Lam1
  • Alexander T. Chao2
  • Calla Martyn3
  • Luying Pei2
  • Debapriya Sengupta2
  • Maxime Dauphinais4
  • Jonathan E. Gable2
  • Srinivasa P. S. Rao2
  • Steffen Renner5
  • W. Armand Guiguemde2
3 more authors
  • Sebastian A. Mikolajczak2
  • Anke Harupa2
  • Gabriel Mitchell1
5 affiliations
  1. 1Open Innovation at Global Health Disease Area, Biomedical Research, Novartis, Emeryville, California, USA
  2. 2Global Health Disease Area, Biomedical Research, Novartis, Emeryville, California, USA
  3. 3Discovery Sciences, Biomedical Research, Novartis, Emeryville, California, USA
  4. 4Global Discovery Chemistry, Biomedical Research, Novartis, Emeryville, California, USA
  5. 5Discovery Sciences, Biomedical Research, Novartis, Basel, Switzerland
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Abstract

The global effort to eradicate malaria requires the development of drugs with novel mechanisms of action and differentiated pharmacological profiles. Both liver and blood phases of Plasmodium infection are essential for disease progression and transmission, making them primary targets for pharmacological intervention. In this study, we established a dual-luciferase reporter assay to simultaneously assess Plasmodium berghei liver-stage development and host cell viability. Screening a library of bioactive small molecules with annotated human targets revealed several inhibitors with potent liver-stage activity and minimal cytotoxicity. Further profiling against Plasmodium falciparum asexual blood stages identified compounds with dual-stage activity, underscoring their potential utility for development as either prophylactic or therapeutic agents. Knowledge of their human targets will facilitate investigation into host- or parasite-directed antimalarial mechanisms, thereby accelerating both biological insight and rational drug development. Our findings constitute a valuable resource for research on malaria biology and the discovery of next-generation antiplasmodials.

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Cite

BibTeXRIS
BibTeX
@article{torres2026screening,
  title = {{Screening of a chemogenetic library unveils dual-stage antiplasmodials with low cytotoxicity}},
  author = {Laura Torres and Matthew E. Fishbaugher and Melanie Lam and Alexander T. Chao and Calla Martyn and Luying Pei and Debapriya Sengupta and Maxime Dauphinais and Jonathan E. Gable and Srinivasa P. S. Rao and Steffen Renner and W. Armand Guiguemde and Sebastian A. Mikolajczak and Anke Harupa and Gabriel Mitchell},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = oct,
  doi = {10.1128/aac.01613-25},
  url = {https://doi.org/10.1128/aac.01613-25},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Screening of a chemogenetic library unveils dual-stage antiplasmodials with low cytotoxicity
AU  - Laura Torres
AU  - Matthew E. Fishbaugher
AU  - Melanie Lam
AU  - Alexander T. Chao
AU  - Calla Martyn
AU  - Luying Pei
AU  - Debapriya Sengupta
AU  - Maxime Dauphinais
AU  - Jonathan E. Gable
AU  - Srinivasa P. S. Rao
AU  - Steffen Renner
AU  - W. Armand Guiguemde
AU  - Sebastian A. Mikolajczak
AU  - Anke Harupa
AU  - Gabriel Mitchell
PY  - 2026
DA  - 2026/10/05
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.01613-25
UR  - https://doi.org/10.1128/aac.01613-25
AB  - The global effort to eradicate malaria requires the development of drugs with novel mechanisms of action and differentiated pharmacological profiles. Both liver and blood phases of Plasmodium infection are essential for disease progression and transmission, making them primary targets for pharmacological intervention. In this study, we established a dual-luciferase reporter assay to simultaneously assess Plasmodium berghei liver-stage development and host cell viability. Screening a library of bioactive small molecules with annotated human targets revealed several inhibitors with potent liver-stage activity and minimal cytotoxicity. Further profiling against Plasmodium falciparum asexual blood stages identified compounds with dual-stage activity, underscoring their potential utility for development as either prophylactic or therapeutic agents. Knowledge of their human targets will facilitate investigation into host- or parasite-directed antimalarial mechanisms, thereby accelerating both biological insight and rational drug development. Our findings constitute a valuable resource for research on malaria biology and the discovery of next-generation antiplasmodials.
SN  - 0066-4804
SN  - 1098-6596
ER  -