Antimalarial cytoskeletal targeting with broad apicomplexan activity

Malaria is a devastating disease that resulted in an estimated 610,000 deaths in 2024, the majority being children under the age of five. Here, we use KNX-115 to illustrate multistage antiparasitic activity upon targeting the cytoskeletal enzyme Plasmodium falciparum myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 traps PfMyoA in a state that binds weakly to actin. A 2.35 Å resolution structure of KNX-115 bound to PfMyoA reveals critical interactions contributing to its mechanism of action. Importantly, in vitro evolution data reveal that KNX-115 engages PfMyoA as a sole cellular target. Inhibiting PfMyoA blocks the development of the blood and liver stages of laboratory strains of P. falciparum , with no liver cell toxicity, sporozoite cell traversal and motility, and sporozoite development in the mosquito. Inhibiting PfMyoA completely kills parasites after 96 h of treatment. Furthermore, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials and shows inhibitory activity against P. falciparum circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of Plasmodium vivax . In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits Cryptosporidium and Eimeria MyoA in vitro and is an effective inhibitor of Cryptosporidium , Toxoplasma, and Eimeria cellular growth, with EC 50 s similar to those found for blood and liver stage Plasmodium .

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-07-24
DOI
https://doi.org/10.1073/pnas.2608709123
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
0.00

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article

Antimalarial cytoskeletal targeting with broad apicomplexan activity

Christoph Mueller‐Dieckmann, Gustave Bergnes, Koen J. Dechering, Benoı̂t Laleu et al.
Proceedings of the National Academy of Sciences
Malaria Research and Control
article

Antimalarial cytoskeletal targeting with broad apicomplexan activity

Christoph Mueller‐Dieckmann, Gustave Bergnes, Koen J. Dechering, Benoı̂t Laleu, Kathleen M. Ruppel, James P. Robblee, Sergio Wittlin, Lorraine Fuller, Partha Mukherjee, Anne Houdusse, L. David Sibley, Dhélio B. Pereira, Nimisha Mittal, Dihia Moussaoui, Tomas Yeo, Stephanie Ouchida, Arnish Chakraborty, James A. Spudich, Anna Caroline Campos Aguiar, Samuel E. Aggrey, Annamma Spudich, Seongwon Jung, David A. Fidock, Darshan V. Trivedi, Rafael V. C. Guido, Elizabeth A. Winzeler, Anastasia Karabina, Heba Wander, Julien Robert‐Paganin, Paul V. Ruijgrok, Rianne van der Laak, Dan Song, Tiantian Jiang, Jin H. Jeon, K M Trybus, Suman Nag, Jeremy N. Burrows, Marianna Akey, Tonnie Huijs, Daisy Chen, Alice Racca, Matthew Freese
article en

Abstract

Malaria is a devastating disease that resulted in an estimated 610,000 deaths in 2024, the majority being children under the age of five. Here, we use KNX-115 to illustrate multistage antiparasitic activity upon targeting the cytoskeletal enzyme Plasmodium falciparum myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 traps PfMyoA in a state that binds weakly to actin. A 2.35 Å resolution structure of KNX-115 bound to PfMyoA reveals critical interactions contributing to its mechanism of action. Importantly, in vitro evolution data reveal that KNX-115 engages PfMyoA as a sole cellular target. Inhibiting PfMyoA blocks the development of the blood and liver stages of laboratory strains of P. falciparum , with no liver cell toxicity, sporozoite cell traversal and motility, and sporozoite development in the mosquito. Inhibiting PfMyoA completely kills parasites after 96 h of treatment. Furthermore, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials and shows inhibitory activity against P. falciparum circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of Plasmodium vivax . In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits Cryptosporidium and Eimeria MyoA in vitro and is an effective inhibitor of Cryptosporidium , Toxoplasma, and Eimeria cellular growth, with EC 50 s similar to those found for blood and liver stage Plasmodium .

Proceedings of the National Academy of SciencesVol. 123(30)
University of Vermont (US), Universidade Federal de Rondônia (BR), Centre National de la Recherche Scientifique (FR), Swiss Tropical and Public Health Institute (CH), University of Georgia (US), University of Basel (CH), Liverpool School of Tropical Medicine (GB), Columbia University Irving Medical Center (US), European Synchrotron Radiation Facility (FR), University of California San Diego (US), Institute of Physics (PL), Institute of Mathematics and Computer Science (MD), LG (India) (IN), Instituto Federal de Educação, Ciência e Tecnologia de Rondônia (BR), Equinox (United States) (US), CNR de la Résistance aux Antibiotiques (FR), TropIQ Health Sciences (NL), Medicines for Malaria Venture (CH), Universidade Federal do Pará (BR), Institut Curie (FR), Universidade Federal de São Paulo (BR)
Bill and Melinda Gates Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, Medicines for Malaria Venture
Good health and well-being
Openalex Percentile: Top 7%
Malaria Research and Control
DOIOpen Access PDFOpenAlex
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