Antimalarial cytoskeletal targeting with broad apicomplexan activity
- Darshan V. Trivedi
- Anastasia Karabina
- Tiantian Jiang
- Daisy Chen
- Nimisha Mittal
- Tonnie Huijs
- Rianne van der Laak
- Jin H. Jeon
- Tomas Yeo
- Dihia Moussaoui
- James P. Robblee
- Marianna Akey
- Matthew Freese
- Lorraine Fuller
- Gustave Bergnes
- Alice Racca
- Heba Wander
- Seongwon Jung
- Stephanie Ouchida
- Paul V. Ruijgrok
- Dan Song
- Annamma Spudich
- Kathleen M. Ruppel
- Suman Nag
- Christoph Mueller-Dieckmann
- Jeremy N. Burrows
- Benoît Laleu
- Rafael Victorio Carvalho Guido
- Anna Caroline Campos Aguiar
- Dhelio Batista Pereira
- Sergio Wittlin
- Partha Mukherjee
- Arnish Chakraborty
- Samuel E. Aggrey
- Julien Robert-Paganin
- Kathleen M. Trybus
- L. David Sibley
- Anne Houdusse
- David A. Fidock
- Koen J. Dechering
- Elizabeth A. Winzeler
- James A. Spudich
2026-07-24
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 .