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<p>Antimalarial therapeutics ideally should target all three major <i>Plasmodium</i> 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.</p>

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Potent acridone antimalarial against all three life stages of Plasmodium

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

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

摘要

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.