Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates
Ángel M. Padilla, Wei Wang, Tsutomu Akama, David S. Carter, Eric E. Easom, Yvonne R. Freund, Jason Halladay, Yang Liu, Sarah A. Hamer, Carolyn L. Hodo, Gregory K. Wilkerson, Dylan Orr, Brooke E. White, Arlene J. George, Huifeng Shen, Yiru Jin, Michael Zhuo Wang, Susanna Tse, Robert T. Jacobs, Rick L. Tarleton
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.