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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Plasmodium falciparum<\/jats:italic>\n                    myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and &gt;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 \u00c5 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\n                    <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                    , 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\n                    <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                    strains resistant to experimental and marketed antimalarials and shows inhibitory activity against\n                    <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                    circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of\n                    <jats:italic toggle=\"yes\">Plasmodium vivax<\/jats:italic>\n                    . In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits\n                    <jats:italic toggle=\"yes\">Cryptosporidium<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Eimeria<\/jats:italic>\n                    MyoA in vitro and is an effective inhibitor of\n                    <jats:italic toggle=\"yes\">Cryptosporidium<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Toxoplasma,<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Eimeria<\/jats:italic>\n                    cellular growth, with EC\n                    <jats:sub>50<\/jats:sub>\n                    s similar to those found for blood and liver stage\n                    <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2608709123","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:38:12Z","timestamp":1784914692000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Antimalarial cytoskeletal targeting with broad apicomplexan activity"],"prefix":"10.1073","volume":"123","author":[{"given":"Darshan V.","family":"Trivedi","sequence":"first","affiliation":[{"name":"Kainomyx Inc.","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Karabina","sequence":"additional","affiliation":[{"name":"Kainomyx Inc.","place":["Palo 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