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 .
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (42)
Darshan V. Trivedi
Kainomyx Inc.
Anastasia Karabina
Kainomyx Inc.
Tiantian Jiang
Department of Pediatrics, School of Medicine, University of California
Daisy Chen
Nimisha Mittal
Department of Pediatrics, School of Medicine, University of California San Diego
Tonnie Huijs
TropIQ Health Sciences
Rianne van der Laak
TropIQ Health Sciences
Jin H. Jeon
Department of Microbiology and Immunology, Columbia University Medical Center
Tomas Yeo
Dihia Moussaoui
Cell Biology and Cancer Unit, Structural Motility, Institut Curie, UMR144 CNRS, Paris Science & Letters Research University
James P. Robblee
Department of Molecular Physiology and Biophysics, University of Vermont
Marianna Akey
Department of Molecular Microbiology, Washington University School of Medicine
Matthew Freese
Department of Molecular Microbiology, Washington University School of Medicine
Lorraine Fuller
Department of Poultry Science, College of Agricultural & Environmental Sciences, University of Georgia
Gustave Bergnes
Kainomyx Inc.
Alice Racca
Kainomyx Inc.
Heba Wander
Kainomyx Inc.
Seongwon Jung
Kainomyx Inc.
Stephanie Ouchida
Kainomyx Inc.
Paul V. Ruijgrok
Kainomyx Inc.
Dan Song
Kainomyx Inc.
Annamma Spudich
Kainomyx Inc.
Kathleen M. Ruppel
Department of Biochemistry, Stanford University School of Medicine
Suman Nag
Kainomyx Inc.
Christoph Mueller-Dieckmann
Structural Biology Group, European Synchrotron Radiation Facility
Jeremy N. Burrows
Benoît Laleu
Medicines for Malaria Venture Medicines for Malaria Venture, International Center Cointrin
Rafael Victorio Carvalho Guido
São Carlos of Physics Institute, University of São Paulo
Anna Caroline Campos Aguiar
Department of Microbiology, Immunology and Parasitology Federal University of São Paulo
Dhelio Batista Pereira
Research Center Tropical Medicine of Rondônia
Sergio Wittlin
Swiss Tropical and Public Health Institute
Partha Mukherjee
The Chatterjee Group Life Sciences Pvt. Ltd.
Arnish Chakraborty
The Chatterjee Group Life Sciences Pvt. Ltd.
Samuel E. Aggrey
Department of Poultry Science, College of Agricultural & Environmental Sciences, University of Georgia
Julien Robert-Paganin
Cell Biology and Cancer Unit, Structural Motility, Institut Curie, UMR144 CNRS, Paris Science & Letters Research University
Kathleen M. Trybus
Department of Molecular Physiology and Biophysics, University of Vermont
L. David Sibley
Anne Houdusse
Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144
David A. Fidock
Department of Microbiology and Immunology, Columbia University Medical Center
Koen J. Dechering
Elizabeth A. Winzeler
James A. Spudich
Department of Biochemistry, Stanford University School of Medicine