Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
28
12
2021
accepted:
21
07
2022
pubmed:
7
9
2022
medline:
1
10
2022
entrez:
6
9
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36065062
doi: 10.1038/s41564-022-01211-y
pii: 10.1038/s41564-022-01211-y
pmc: PMC9519446
mid: EMS151388
doi:
Substances chimiques
Prodrugs
0
Trypanocidal Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1536-1546Subventions
Organisme : Wellcome Trust
ID : 104059
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI125738
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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