Potent acridone antimalarial against all three life stages of Plasmodium
Abstract
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.
Article Details
Authors (58)
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
Charité Center for Global Health, Institute of International Health, Charité–Universitätsmedizin Berlin
Welmoed van Loon
Charité Center for Global Health, Institute of International Health, Charité–Universitätsmedizin Berlin
Jules M. Ndoli
Heather Kudyba
Joel Vega-Rodriguez
Martin Okitwi
Infectious Disease Research Collaboration, Kampala, Uganda
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
University of California, San Francisco, San Francisco
Michael K. Riscoe
Roland A. Cooper
Alison Roth
Jane X. Kelly