Identification of UCB-9721 as a potent inhibitor of MyoA, the essential class XIV myosin motor of apicomplexan parasites
Year: 2026
Type: preprint
Abstract: The virulence of Toxoplasma gondii and other apicomplexan parasites relies on a unique form of cellular motility driven by MyoA, an unconventional class XIV myosin motor protein. To identify new chemical probes for investigating the molecular mechanisms of parasite motility, we screened over 50,000 small molecules for inhibitors of T. gondii MyoA (TgMyoA). The top hit from the screen, UCB-9721, is almost 40-fold more potent as an inhibitor of TgMyoA actin-activated ATPase activity than the previously described TgMyoA inhibitor, KNX-002, and 45-fold more potent at inhibiting parasite motility, with no detectable toxicity towards mammalian cells. UCB-9721 also inhibited the motility and/or growth of the related apicomplexan parasites Plasmodium falciparum, Cryptosporidium parvum, and Babesia duncani, suggesting that this compound will be a useful new chemical probe for studying motility and MyoA function in apicomplexan parasites more broadly. While UCB-9721 and KNX-002 were identified independently, they share a similar chemical scaffold. To determine why UCB-9721 is so much more potent than KNX-002 and to inform future development of this inhibitor class, we undertook comparative molecular docking analyses, targeted TgMyoA mutagenesis, and a directed structure-activity relationship analysis. The results identified the sulfonamide group of UCB-9721 and its hydrogen bond interactions with R249, E275 and a stabilized water network within the TgMyoA binding pocket as key to the compound’s increased potency. Further development of UCB-9721, informed by the results presented here, may transform this promising new chemical class into actionable drug development leads against this important group of human and animal pathogens.
Authors: Anne K Snyder, Filomena Tedesco, Anne Kelsen, Eddie Wehri, Binod Nepal, Jose Teixeira, Emmett Dews, Sachie Kanatani, Kyle Kasprzak, Jonathan Oliva, Kaesi Morelli, Samantha Beck Previs, Bruno Martorelli di Genova, Fran Sverdrup, Martin J Boulanger, Photini Sinnis, Christopher D Huston, Sandhya Kortagere, David M Warshaw, Julia Schaletzky, Nicholas J Westwood, Gary E Ward
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Image-based quantification of Plasmodium sporozoites in a single oocyst using deep learning-based segmentation and 3D reconstruction, Investigating the Mechanisms Underlying Mosquito Infectiousness in Malaria, Liquid chromatography and mass spectrometry instrument system, Multiscale analysis of MyosinA-based motility in Toxoplasma gondii, G-Protein Linked Signaling Pathways in Chemotaxis, Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions., The Biochemical Basis for the Mechanics of Cytokinesis, Vermont Immunology / Infectious Diseases Training Grant
OpenAlex ID: W7165372253