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Peer-reviewedCC BY-NC-ND 4.0International Journal for Parasitology: Drugs and Drug Resistance

Repurposed small-molecule inhibitors of Plasmodium falciparum calmodulins disrupt calcium homeostasis

  • Alma Tammour1,2
  • Sadaf Parveen1
  • Ashutosh Panda1
  • Shahnawaz Ahmad3
  • Madiha Abbas4
  • Hari Madhav5
  • Zainab Khan4
  • Anisha Thalor1
  • Pragyan Parimita Rath4
  • Neha Prakash4
  • Iqbal Taily Junaid1
  • Osama Mukhtar1
3 more authors
  • Dinesh Gupta3
  • Asif Mohmmed4
  • Pawan Malhotra1
5 affiliations
  1. 1Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
  2. 2Department of Biochemistry and Microbiology, Faculty of Pharmacy, Homs University, Syria
  3. 3Translational Bioinformatic Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, 110067, India
  4. 4Parasite Cell Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, 110067, India
  5. 5Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, 110067, India
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Abstract

Calcium signaling is essential for the survival of Plasmodium falciparum, yet few components of its Ca2+ regulatory machinery have been chemically validated as antimalarial drug targets. Here, we report the structure-guided identification of small molecule inhibitors targeting a parasite specific subset of calmodulin and calmodulin-like proteins that lack close human orthologs. Virtual screening followed by biophysical validation revealed that the drugs Econazole, Carvedilol, and Deschloro-Lapatinib selectively engage three parasite calmodulin paralogs (PfCam200, PfCam300, and PfCam400) and inhibit their Ca2+-binding activity. Direct binding was confirmed by bio-layer interferometry and calcium-binding assays, demonstrating micromolar affinities and functional inhibition. Chemical perturbation of parasite calmodulins disrupts food vacuole directed Ca2+ trafficking, induces redistribution of intracellular Ca2+, and results in stage specific arrest of parasite development. Confocal imaging localizes PfCam200, PfCam300, and PfCam400 in proximity to the digestive vacuole transporters PfCRT and PfMDR1, supporting a mechanistic link between calmodulin function and vacuolar Ca2+ homeostasis. Collectively, these findings establish parasite calmodulins as chemically tractable targets and demonstrate the utility of repurposed small molecules as probes to interrogate essential Ca2+-dependent pathways in malaria parasites.

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Cite

BibTeXRIS
BibTeX
@article{tammour2026repurposed,
  title = {{Repurposed small-molecule inhibitors of Plasmodium falciparum calmodulins disrupt calcium homeostasis}},
  author = {Alma Tammour and Sadaf Parveen and Ashutosh Panda and Shahnawaz Ahmad and Madiha Abbas and Hari Madhav and Zainab Khan and Anisha Thalor and Pragyan Parimita Rath and Neha Prakash and Iqbal Taily Junaid and Osama Mukhtar and Dinesh Gupta and Asif Mohmmed and Pawan Malhotra},
  journal = {International Journal for Parasitology: Drugs and Drug Resistance},
  year = {2026},
  month = oct,
  doi = {10.1016/j.ijpddr.2026.100673},
  url = {https://doi.org/10.1016/j.ijpddr.2026.100673},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Repurposed small-molecule inhibitors of Plasmodium falciparum calmodulins disrupt calcium homeostasis
AU  - Alma Tammour
AU  - Sadaf Parveen
AU  - Ashutosh Panda
AU  - Shahnawaz Ahmad
AU  - Madiha Abbas
AU  - Hari Madhav
AU  - Zainab Khan
AU  - Anisha Thalor
AU  - Pragyan Parimita Rath
AU  - Neha Prakash
AU  - Iqbal Taily Junaid
AU  - Osama Mukhtar
AU  - Dinesh Gupta
AU  - Asif Mohmmed
AU  - Pawan Malhotra
PY  - 2026
DA  - 2026/10/17
JO  - International Journal for Parasitology: Drugs and Drug Resistance
DO  - 10.1016/j.ijpddr.2026.100673
UR  - https://doi.org/10.1016/j.ijpddr.2026.100673
AB  - Calcium signaling is essential for the survival of Plasmodium falciparum, yet few components of its Ca2+ regulatory machinery have been chemically validated as antimalarial drug targets. Here, we report the structure-guided identification of small molecule inhibitors targeting a parasite specific subset of calmodulin and calmodulin-like proteins that lack close human orthologs. Virtual screening followed by biophysical validation revealed that the drugs Econazole, Carvedilol, and Deschloro-Lapatinib selectively engage three parasite calmodulin paralogs (PfCam200, PfCam300, and PfCam400) and inhibit their Ca2+-binding activity. Direct binding was confirmed by bio-layer interferometry and calcium-binding assays, demonstrating micromolar affinities and functional inhibition. Chemical perturbation of parasite calmodulins disrupts food vacuole directed Ca2+ trafficking, induces redistribution of intracellular Ca2+, and results in stage specific arrest of parasite development. Confocal imaging localizes PfCam200, PfCam300, and PfCam400 in proximity to the digestive vacuole transporters PfCRT and PfMDR1, supporting a mechanistic link between calmodulin function and vacuolar Ca2+ homeostasis. Collectively, these findings establish parasite calmodulins as chemically tractable targets and demonstrate the utility of repurposed small molecules as probes to interrogate essential Ca2+-dependent pathways in malaria parasites.
SN  - 2211-3207
ER  -