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
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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.