Antimalarial cytoskeletal targeting with broad apicomplexan activity
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 .
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BibTeX
@article{trivedi2026antimalarial,
title = {{Antimalarial cytoskeletal targeting with broad apicomplexan activity}},
author = {Darshan Trivedi and Anastasia Karabina and Tiantian Jiang and Daisy Chen and Nimisha Mittal and Tonnie Huijs and Rianne van der Laak and Jin Jeon and Tomas Yeo and Dihia Moussaoui and James Robblee and Marianna Akey and Matthew Freese and Lorraine Fuller and Gustave Bergnes and Alice Racca and Heba Wander and Seongwon Jung and Stephanie Ouchida and Paul Ruijgrok and Dan Song and Annamma Spudich and Kathleen Ruppel and Suman Nag and Christoph Mueller-Dieckmann and Jeremy Burrows and Benoît Laleu and Rafael Victorio Carvalho Guido and Anna Caroline Campos Aguiar and Dhelio Batista Pereira and Sergio Wittlin and Partha Mukherjee and Arnish Chakraborty and Samuel Aggrey and Julien Robert-Paganin and Kathleen Trybus and L. David Sibley and Anne Houdusse and David Fidock and Koen Dechering and Elizabeth Winzeler and James Spudich},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = jul,
doi = {10.1073/pnas.2608709123},
url = {https://hal.science/hal-05765366v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Antimalarial cytoskeletal targeting with broad apicomplexan activity
AU - Darshan Trivedi
AU - Anastasia Karabina
AU - Tiantian Jiang
AU - Daisy Chen
AU - Nimisha Mittal
AU - Tonnie Huijs
AU - Rianne van der Laak
AU - Jin Jeon
AU - Tomas Yeo
AU - Dihia Moussaoui
AU - James Robblee
AU - Marianna Akey
AU - Matthew Freese
AU - Lorraine Fuller
AU - Gustave Bergnes
AU - Alice Racca
AU - Heba Wander
AU - Seongwon Jung
AU - Stephanie Ouchida
AU - Paul Ruijgrok
AU - Dan Song
AU - Annamma Spudich
AU - Kathleen Ruppel
AU - Suman Nag
AU - Christoph Mueller-Dieckmann
AU - Jeremy Burrows
AU - Benoît Laleu
AU - Rafael Victorio Carvalho Guido
AU - Anna Caroline Campos Aguiar
AU - Dhelio Batista Pereira
AU - Sergio Wittlin
AU - Partha Mukherjee
AU - Arnish Chakraborty
AU - Samuel Aggrey
AU - Julien Robert-Paganin
AU - Kathleen Trybus
AU - L. David Sibley
AU - Anne Houdusse
AU - David Fidock
AU - Koen Dechering
AU - Elizabeth Winzeler
AU - James Spudich
PY - 2026
DA - 2026/07/24
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2608709123
UR - https://hal.science/hal-05765366v1
AB - 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 .
SN - 0027-8424
SN - 1091-6490
ER -