Faculty, Staff and Student Publications
Publication Date
10-1-2022
Journal
Nature Microbiology
DOI
10.1038/s41564-022-01211-y
PMID
36065062
PMCID
PMC9519446
PubMedCentral® Posted Date
9-5-2022
PubMedCentral® Full Text Version
Post-print
Abstract
Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease.
Keywords
Animals, Chagas Disease, Primates, Prodrugs, Trypanocidal Agents, Trypanosoma cruzi
Published Open-Access
yes
Recommended Citation
Padilla, Angel M; Wang, Wei; Akama, Tsutomu; et al., "Discovery of an Orally Active Benzoxaborole Prodrug Effective in the Treatment of Chagas Disease in Non-Human Primates" (2022). Faculty, Staff and Student Publications. 4769.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4769
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