Sponsor
This work was supported by NIH/NIAID (award numbers AI158533 to J.X.K.; AI075045 and AI139179 to P.J.R.; AI181593 to L.C.; and AI127338 to M.T.F.), DOD/PRMRP (award number W81XWH2210494 to J.X.K.), and US Department of Veterans Affairs (VA Merit Review Award BX004522 to J.S.D., and BX005674 to J.X.K.). The National Science Foundation (NSF) is acknowledged for support of the BioAnalytical Mass Spectrometry Facility at Portland State University (MRI1828573). This research was also supported in part by an appointment to the Department of Defense (DoD) Research Participation Program administered by Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between U.S. Department of Energy (DOE) and the DOD. ORISE is managed by ORAU under DOE contract number DE-SC0014664. In addition, this work was supported by the NIH Distinguished Scholars Program and the Intramural Research Program of the Division of Intramural Research (AI001250-01), NIAID/NIH to J.V.R. We acknowledge Dr. Amrendra Kumar for assistance with HRMS and HPLC analyses, and Dr. David Peyton for valuable scientific discussions. Procurement of ART-resistant clinical isolates was supported by German Research Foundation (DFG; ref no. GRK2046, and GRK2290). Material has been reviewed by the WRAIR. There is no objection to its presentation and/or publication.
Published In
Research Square
Document Type
Pre-Print
Publication Date
6-27-2025
Subjects
Malaria -- Prevention -- Research
Abstract
New antimalarial therapeutics ideally should target all three major life cycle stages. Here we present an acridone antimalarial chemotype that is potent against blood, liver, and mosquito stages of malaria parasites, with the potential for single-dose cure of bloodstream infections, radical cure of liver infections, and blocking of transmission to mosquitoes. Attributes of lead candidate T111 include potent in vitro activity against cultured parasites, ex vivo activity against clinical isolates, oral single dose cure in an asexual blood stage rodent model, inhibition of sexual blood stage parasites, activity against relapsing parasites in non-human primate liver cells, prevention of parasite development in mosquitoes, and synergy in combination with tafenoquine against blood and liver stage parasites. Analysis of parasites selected for resistance to T111 suggested inhibition of the mitochondrial electron transport chain, with a mechanism distinct from that of other antimalarials in use or under development. Safety profiles, including toxicology evaluations in rats, showed a favorable therapeutic index. Overall, T111 emerges as a promising candidate for treatment and prevention of malaria.
Rights
© Copyright the author(s) 2025
Locate the Document
DOI
10.21203/rs.3.rs-6858328/v1
Persistent Identifier
https://archives.pdx.edu/ds/psu/44011
Publisher
Springer Science and Business Media LLC
Citation Details
Published as: Kelly, J., Kancharla, P., Dodean, R., Li, Y., Zhang, X., Kelly, S., Charlton, J., Binauhan, A., Garcia, L., Caridha, D., Madejczyk, M., Jin, X., Dennis, W., Kudyba, K., McEnearney, S., Lee, P., Blount, C., DeLuca, J., Vuong, C., … Roth, A. (2025). Potent Acridone Antimalarial against All Three Life Stages of Plasmodium.
Description
This is the author’s version of a work that was accepted for publication. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published as: Potent Acridone Antimalarial against All Three Life Stages of Plasmodium.