Year: 2026
Type: article
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.
Source: Nature Communications
Authors: 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
Institutions: Portland State University, Portland VA Medical Center, Dominican University of California, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Walter Reed Army Institute of Research, University of South Florida, University of Notre Dame, Humboldt-Universität zu Berlin, Freie Universität Berlin, Charité – Universitätsmedizin Berlin, University of Rwanda, University Teaching Hospital of Butare, Infectious Diseases Research Collaboration, University of California, San Francisco, SRI International, The University of Melbourne, Harvard University, Oregon Health & Science University, Howard Hughes Medical Institute, VA Portland Health Care System
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Defense, U.S. Department of Energy, U.S. Department of Veterans Affairs, Oak Ridge Associated Universities, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Portland State University, National Institutes of Health, Oak Ridge Institute for Science and Education, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
Awards: G1104668110, G1775075938, G2848141657, Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies, Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies in Uganda, G473123490, G515206079, G601061201, PRECLINICAL DEVELOPMENT OF NOVEL LIVER-STAGE ACTIVE ANTIMALARIALS WITH RADICAL CURE POTENTIAL, G7583022941, G7619220232, G8570346810, Malaria transmission blocking through mosquito contact with treated surfaces, G9000270008, G9000324778, Second-Generation Novel Liver Stage Active Antimalarials, Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline, The Graduate Program in Tropical Infectious Diseases, Unraveling the Drivers of Persistent Malaria Transmission in Cameroon: A Systems Approach (REDIAL), G977291288
OpenAlex ID: W7154330640