Antimalarial cytoskeletal targeting with broad apicomplexan activity.

  • Journal Article
Journal:
Proceedings of the National Academy of Sciences of the United States of America, Volume: 123, Issue: 30
Published:
July 28, 2026
PMID:
42497201
Authors:
Darshan V Trivedi DV, Anastasia Karabina A, Tiantian Jiang T, Daisy Chen D, Nimisha Mittal N, Tonnie Huijs T, Rianne van der Laak R, Jin H Jeon JH, Tomas Yeo T, Dihia Moussaoui D, James P Robblee JP, Marianna Akey M, Matthew Freese M, Lorraine Fuller L, Gustave Bergnes G, Alice Racca A, Heba Wander H, Seongwon Jung S, Stephanie Ouchida S, Paul V Ruijgrok PV, Dan Song D, Annamma Spudich A, Kathleen M Ruppel KM, Suman Nag S, Christoph Mueller-Dieckmann C, Jeremy N Burrows JN, Benoît Laleu B, Rafael Victorio Carvalho Guido RVC, Anna Caroline Campos Aguiar AC, Dhelio Batista Pereira DB, Sergio Wittlin S, Partha Mukherjee P, Arnish Chakraborty A, Samuel E Aggrey SE, Julien Robert-Paganin J, Kathleen M Trybus KM, L David Sibley LD, Anne Houdusse A, David A Fidock DA, Koen J Dechering KJ, Elizabeth A Winzeler EA, James A Spudich JA
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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 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 , 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 strains resistant to experimental and marketed antimalarials and shows inhibitory activity against circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of . In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits and MyoA in vitro and is an effective inhibitor of , and cellular growth, with ECs similar to those found for blood and liver stage .

Courtesy of the U.S. National Library of Medicine