Potent acridone antimalarial against all three life stages of Plasmodium

Antimalarial therapeutics ideally should target all three major Plasmodium life cycle stages. Here we present an acridone antimalarial chemotype that is potent against blood, liver, and mosquito stages of malaria parasites. 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 suggests inhibition of the mitochondrial electron transport chain, with a mechanism distinct from that of other antimalarials in use or under development. The safety profile of T111, including toxicology evaluations in rats, absence of hemolytic toxicity, and low genotoxicity and cardiotoxicity potential, demonstrates a favorable therapeutic index. Overall, T111 emerges as a promising candidate for treatment and prevention of malaria, with potential for single-dose cure of bloodstream infections, radical cure of liver infections, and interruption of transmission to mosquitoes.

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Publication Details

Journal
Nature Communications
Published
2026-04-14
DOI
https://doi.org/10.1038/s41467-026-71708-1
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
0.00

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article

Potent acridone antimalarial against all three life stages of Plasmodium

Frank P. Mockenhaupt, Roland A. Cooper, Liwang Cui, Diana Caridha et al.
Nature Communications
Malaria Research and Control
article

Potent acridone antimalarial against all three life stages of Plasmodium

Frank P. Mockenhaupt, Roland A. Cooper, Liwang Cui, Diana Caridha, Brandon Pybus, Tarrick Qahash, Michael K. Riscoe, Jane X. Kelly, Geoffrey C Chin, Aaron Nilsen, Susan E. Leed, Welmoed van Loon, Cameron Blount, Michael S. Madejczyk, Joel Vega-Rodríguez, Flaminia Catteruccia, Papireddy Kancharla, Geoffrey I. McFadden, Karl Kudyba, Heather M. Kudyba, Martin Okitwi, Douglas A. Shoue, Alexandra S. Probst, Jon C. Mirsalis, Jinghua Lu, Rozalia A. Dodean, Anongruk Chim-Ong, P. Holland Alday, Michael T. Ferdig, Alison Roth, J. Stone Doggett, Philip J. Rosenthal, S. A. Farrell, Chau Vuong, Oriana Kreutzfeld, Jianbing Mu, Patricia Lee, Christopher D. Goodman, Carol Green, Mónica L. Martin, Jordan Charlton, William E. Dennis, Kristina Pannone, Sharon McEnearney, Kennedy Mdaki, Aaron Agulay, Angely J. Binauhan, Kimberly Navarrete, Jules M. Ndoli, Xiannu Jin, Sean Kelly, Laurize Garcia, Ying Liu, Xiaowei Zhang, Yuexin Li, Cristina Docan, Jesse DeLuca, Hieu T. Dinh
article en

Abstract

Antimalarial therapeutics ideally should target all three major Plasmodium life cycle stages. Here we present an acridone antimalarial chemotype that is potent against blood, liver, and mosquito stages of malaria parasites. 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 suggests inhibition of the mitochondrial electron transport chain, with a mechanism distinct from that of other antimalarials in use or under development. The safety profile of T111, including toxicology evaluations in rats, absence of hemolytic toxicity, and low genotoxicity and cardiotoxicity potential, demonstrates a favorable therapeutic index. Overall, T111 emerges as a promising candidate for treatment and prevention of malaria, with potential for single-dose cure of bloodstream infections, radical cure of liver infections, and interruption of transmission to mosquitoes.

Nature Communications
University of Notre Dame (US), Portland State University (US), SRI International (US), Howard Hughes Medical Institute (US), Harvard University (US), Oregon Health & Science University (US), The University of Melbourne (AU), Dominican University of California (US), University of California, San Francisco (US), University of South Florida (US), Veterans Health Administration (US), Portland VA Medical Center (US), Humboldt-Universität zu Berlin (DE), University of Rwanda (RW), Infectious Diseases Research Collaboration (UG), National Institute of Allergy and Infectious Diseases (US), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), University Teaching Hospital of Butare (RW), Walter Reed Army Institute of Research (US)
U.S. Department of Defense, U.S. Department of Veterans Affairs, Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Responsible consumption and production, Zero hunger
Openalex Percentile: Top 20%
Malaria Research and Control
DOIOpen Access PDFOpenAlex
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