Proceedings of the National Academy of Sciences of the United States of America · 2026
Antimalarial cytoskeletal targeting with broad apicomplexan activity.
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Trivedi Darshan V, Karabina Anastasia, Jiang Tiantian, Chen Daisy, Mittal Nimisha, Huijs Tonnie, van der Laak Rianne, Jeon Jin H, Yeo Tomas, Moussaoui Dihia, Robblee James P, Akey Marianna, Freese Matthew, Fuller Lorraine, Bergnes Gustave, Racca Alice, Wander Heba, Jung Seongwon, Ouchida Stephanie, Ruijgrok Paul V, Song Dan, Spudich Annamma, Ruppel Kathleen M, Nag Suman, Mueller-Dieckmann Christoph, Burrows Jeremy N, Laleu Benoît, Guido Rafael Victorio Carvalho, Campos Aguiar Anna Caroline, Pereira Dhelio Batista, Wittlin Sergio, Mukherjee Partha, Chakraborty Arnish, Aggrey Samuel E, Robert-Paganin Julien, Trybus Kathleen M, Sibley L David, Houdusse Anne, Fidock David A, Dechering Koen J, Winzeler Elizabeth A, Spudich James A
Аннотация
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 EC50s similar to those found for blood and liver stage Plasmodium.