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Updated: Aug 6, 2026
07:14
Ookluc: A Plasmodium berghei Line for Identifying Transmission-blocking Compounds
Published on: July 11, 2025
Antimalarial cytoskeletal targeting with broad apicomplexan activity
Darshan V Trivedi1, Anastasia Karabina1, Tiantian Jiang2
1Kainomyx Inc., Palo Alto, CA 94304.
Summary
A new drug, KNX-115, effectively targets Plasmodium falciparum myosin A (PfMyoA), a key enzyme in malaria parasites. This discovery offers a promising new avenue for malaria treatment by inhibiting parasite growth across multiple stages.
Area of Science:
- Parasitology
- Drug Discovery
- Structural Biology
Background:
- Malaria caused 610,000 deaths in 2024, disproportionately affecting young children.
- Targeting essential parasite enzymes is a key strategy for developing new antimalarials.
- Plasmodium falciparum myosin A (PfMyoA) is a crucial cytoskeletal enzyme for parasite survival.
Purpose of the Study:
- To investigate the antiparasitic activity of KNX-115 against Plasmodium falciparum.
- To elucidate the mechanism of action of KNX-115 by determining its binding structure to PfMyoA.
- To assess the efficacy of KNX-115 against drug-resistant malaria strains and other apicomplexan parasites.
Main Methods:
- Biochemical assays to measure inhibition of actin-activated ATPase activity.
- X-ray crystallography to determine the structure of KNX-115 bound to PfMyoA.
- In vitro evolution studies to confirm PfMyoA as the sole cellular target.
- In vitro testing against various Plasmodium strains, including resistant isolates and Plasmodium vivax.
- In vitro assays against Cryptosporidium, Eimeria, and Toxoplasma gondii.
Main Results:
- KNX-115 potently inhibits purified PfMyoA (low nanomolar) with high selectivity over human myosins.
- The 2.35 Å crystal structure reveals key interactions of KNX-115 with PfMyoA, trapping it in a weak actin-binding state.
- KNX-115 demonstrates broad-spectrum efficacy, inhibiting blood and liver stages of P. falciparum, including drug-resistant strains and P. vivax.
- The compound also shows inhibitory activity against Cryptosporidium, Eimeria, and Toxoplasma cellular growth.
Conclusions:
- KNX-115 is a potent, selective inhibitor of Plasmodium falciparum myosin A (PfMyoA) with multistage antiparasitic activity.
- The drug effectively targets both drug-sensitive and drug-resistant malaria parasites, as well as other apicomplexan pathogens.
- KNX-115 represents a promising new therapeutic candidate for malaria and potentially other apicomplexan-caused diseases.
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