A small-molecule myosin inhibitor as a targeted multi-stage antimalarial
Trivedi, D. V.; Karabina, A.; Bergnes, G.; Racca, A.; Wander, H.; Jung, S.; Mittal, N.; Huijs, T.; Ouchida, S.; Ruijgrok, P. V.; Song, D.; Wittlin, S.; Mukherjee, P.; Chakraborty, A.; Winzeler, E. A.; Burrows, J. N.; Laleu, B.; Spudich, A.; Ruppel, K.; Dechering, K.; Nag, S.; Spudich, J.
Show abstract
Malaria is a devastating disease that resulted in an estimated 627,000 deaths in 2020. About 80% of those deaths were among children under the age of five. Our approach is to develop small molecule inhibitors against cytoskeletal targets that are vital components of parasite function, essential at multiple stages of parasite infection, can be targeted with high specificity, and are highly druggable. Here we describe KNX-115, which inhibits purified Plasmodium falciparum myosin A (PfMyoA) actin-activated ATPase with a potency in the 10s of nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 inhibits the blood and liver stages of Plasmodium with an EC50 of about 100 nanomolar, with negligible liver cell toxicity. In addition, KNX-115 inhibits sporozoite cell traversal and blocks the gametocyte to oocyst conversion in the mosquito. KNX-115 displays a similar killing profile to pyrimethamine and parasites are totally killed after 96 hours of treatment. In line with its novel mechanism of action, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials. In vitro evolution data likely suggests a refractory potential of KNX-115 in developing parasite resistance.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites 96%
- Highly accurate protein structure prediction-based virtual docking pipeline accelerating the identification of anti-schistosomal compounds 94%
- The Plasmepsin-Piperaquine Paradox Persists 94%
Similar papers in this journal
- Screening the Pathogen Box Compounds for Activity Against Plasmodium falciparum Sporozoite Motility 97%
- Characterization of antimalarial activity of artemisinin-based hybrid drugs 97%
- Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection 96%
Similar papers in this journal
- Quorum sensing N-Acyl homoserine lactones are a new class of anti-schistosomal. 95%
- The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets 94%
- De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells 94%
Similar papers in this journal
- Measuring Growth, Resistance and Recovery after Artemisinin Treatment of Plasmodium falciparum in a semi-high-throughput Assay 93%
- Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi 92%
- Efficacy and safety of dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in Northern Papua and Jambi, Indonesia 92%
Similar papers in this journal
- A pyridyl-furan series developed from Open Global Health Library blocks red blood cell invasion and protein trafficking in Plasmodium falciparum through potential inhibition of the parasites PI4KIIIb enzyme. 96%
- Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action 96%
- Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi, Heligmosomoides polygyrus and Schistosoma mansoni 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.